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Riboflavin transporter deficiency (RTD), previously referred to as Brown-Vialetto-Van Laere syndrome, is caused by pathogenic variants in the SLC52A1 , SLC52A2 , or SLC52A3 genes, resulting in RTD types 1, 2, and 3, respectively. Researchers estimate an occurrence of approximately 1 in 1,000,000. There is only one case of type 1 described in medical literature. Type 2 is characterized by muscle weakness in the arms and neck, vision loss, hearing impairment, and sensory ataxia. In type 3, vocal cord paralysis is more common and muscle weakness is more generalized. In 2018, we described a case of a 6-year-old girl with RTD type 2 who made remarkable visual recovery after initiation of treatment with oral riboflavin and coenzyme Q10 supplementation. The patient's younger brother began the same treatment regimen after genetic testing confirmed that he carried the same genetic variant. In this report, we update the visual and neurologic status in these siblings 5 years after our initial report and 7.5 years after initiation of riboflavin treatment.

Background: Leber hereditary optic neuropathy (LHON) is one of the more common mitochondrial diseases and is rarely associated with mitochondrial renal disease. We report 3 unrelated patients with a background of adult-onset renal failure who presented to us with LHON and were shown to have a heteroplasmic mitochondrial DNA mutation (m.13513G>A)., Methods: Retrospective chart review., Results: All 3 patients had a background of chronic renal failure and presented to us with bilateral optic neuropathy (sequential in 2) and were found to have heteroplasmic m.13513G>A mutations in the MT-ND5 gene. Two of the patients were females (aged 30 and 45 years) with chronic kidney disease from their 20s, attributed to pre-eclampsia, one of whom also had diabetes and sudden bilateral hearing loss. One patient was a male (aged 54 years) with chronic kidney disease from his 20s attributed to IgA nephropathy. His mother had diabetes and apparently sudden bilateral blindness in her 70s. Renal biopsy findings were variable and included interstitial fibrosis, acute tubular necrosis, focal segmental glomerulosclerosis, and IgA/C3 tubular casts on immunofluorescence. Mild improvements in vision followed treatment with either idebenone or a combination supplement including coenzyme Q10, alpha-lipoic acid, and B vitamins., Conclusions: Our cases expand the clinical syndromes associated with m.13513G>A to include bilateral optic neuropathy and adult-onset renal disease. This highlights that in patients with bilateral, especially sequential, optic neuropathy a broad approach to mitochondrial testing is more useful than a limited LHON panel. Mitochondrial diseases present a diagnostic challenge because of their clinical and genetic variability., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 by North American Neuro-Ophthalmology Society.)

To explore the efficacy and safety of butylphthalide combined with idebenone in the treatment of vascular dementia. The clinical data of 126 patients with vascular dementia who were admitted to our hospital between March 2021 and February 2023 were retrospectively reviewed. Among them, 62 patients received butylphthalide alone (single group) and 64 patients received butylphthalide combined with idebenone (combined group). Cognitive function scores, serum inflammatory factor levels, oxidative stress index levels, and incidence of adverse reactions were compared between the 2 groups before and after treatment. After treatment, the Hasegawa Dementia Scale, Mini Mental State Examination Scale, and activities of daily living scores in both groups were higher than before treatment, and the scores in the combined group were higher than before treatment (P < .05). After treatment, the levels of serum C-reactive protein, tumor necrosis factor-α, and interleukin 6 in both groups were lower than those before treatment, and those in the combined group were lower than those in the simple group (P < .05). After treatment, the levels of serum glutathione peroxidase and superoxide dismutase in the 2 groups were higher than those before treatment, and the level of malondialdehyde was lower than that before treatment. The levels of serum glutathione peroxidase and superoxide dismutase in the combined group were higher than those in the simple group, and the level of malondialdehyde was lower than that in the simple group (P < .05). There was no significant difference in the incidence of adverse reactions between the combined group (6.25%) and the simple group (3.23%) (P > .05). Compared with butylphthalide alone, intervention of butylphthalide combined with idebenone on vascular dementia can effectively reduce the degree of inflammatory and oxidative stress reactions, improve cognitive function, and promote the ability to perform activities of daily living in a safe manner., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Rationale: Progressive encephalopathy with brain edema and/or leukoencephalopathy-1 is an infantile, lethal neurometabolic disorder caused by a NAD(P)HX epimerase (NAXE) gene mutation. It is characterized by a fluctuating disease course with repeated episodes of improvement and regression. In this report, we present a rare case of NAXE gene mutation-related encephalopathy with unexpected neurological recovery and long survival time., Patient Concerns: A 20-month-old girl presented with progressively unsteady gait and bilateral hand tremors after a trivial febrile illness. Her disease rapidly progressed to consciousness disturbance, 4-limb weakness (muscle power: 1/5 on the Medical Research Council scale), and respiratory failure. The patient gradually recovered 2 months later. However, another episode of severe fever-induced encephalopathy developed 2 years after the initial presentation., Diagnoses: Results of laboratory investigations, including complete blood count, blood chemistry, inflammatory markers, and cerebral spinal fluid analysis were unremarkable. Electroencephalography and nerve conduction velocity studies yielded normal results. Brain magnetic resonance imaging on diffusion-weighted imaging revealed abnormal sysmmetric hyperintensity in the bilateral middle cerebellar peduncles. A genetic study using whole exome sequencing confirmed the diagnosis of NAXE gene mutation-related encephalopathy., Interventions: Pulse therapy with methylprednisolone, intravenous immunoglobulin, coenzyme Q10, and carnitine were initially introduced. After a NAXE gene defect was detected, the vitamin B complex and coenzyme Q10 were administered. A continuous rehabilitation program was also implemented., Outcomes: NAXE gene mutation-related encephalopathy is usually regarded as a lethal neurometabolic disorder. However, the outcome in this case is better than that in the previous cases. She showed progressive neurological recovery and a longer survival time. The muscle power of the 4 limbs recovered to grade 4. At present (age of 5.5 years old), she can walk with an unsteady gait and go to school., Lessons: Although NAXE gene mutation-related encephalopathy is rare, it should be considered as a differential diagnosis of early onset progressive encephalopathy., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Leber hereditary optic neuropathy (LHON) leads to bilateral central vision loss. In a clinical trial setting, idebenone has been shown to be safe and to provide a trend toward improved visual acuity, but long-term evidence of effectiveness in real-world clinical practice is sparse., Methods: Open-label, multicenter, retrospective, noncontrolled analysis of long-term visual acuity and safety in 111 LHON patients treated with idebenone (900 mg/day) in an expanded access program. Eligible patients had a confirmed mitochondrial DNA mutation and had experienced the onset of symptoms (most recent eye) within 1 year before enrollment. Data on visual acuity and adverse events were collected as per normal clinical practice. Efficacy was assessed as the proportion of patients with either a clinically relevant recovery (CRR) or a clinically relevant stabilization (CRS) of visual acuity. In the case of CRR, time to and magnitude of recovery over the course of time were also assessed., Results: At time of analysis, 87 patients had provided longitudinal efficacy data. Average treatment duration was 25.6 months. CRR was observed in 46.0% of patients. Analysis of treatment effect by duration showed that the proportion of patients with recovery and the magnitude of recovery increased with treatment duration. Average gain in best-corrected visual acuity for responders was 0.72 logarithm of the minimal angle of resolution (logMAR), equivalent to more than 7 lines on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. Furthermore, 50% of patients who had a visual acuity below 1.0 logMAR in at least one eye at initiation of treatment successfully maintained their vision below this threshold by last observation. Idebenone was well tolerated, with most adverse events classified as minor., Conclusions: These data demonstrate the benefit of idebenone treatment in recovering lost vision and maintaining good residual vision in a real-world setting. Together, these findings indicate that idebenone treatment should be initiated early and be maintained more than 24 months to maximize efficacy. Safety results were consistent with the known safety profile of idebenone.

Background: Polycystic ovary syndrome (PCOS) is one of the common gynecological endocrine system diseases. It is characterized by excessive androgen, rare or anovulation, and polycystic ovary morphology. Coenzyme Q10 (CoQ10) is a fat-soluble natural vitamin, which has a continuous oxidation-reduction cycle and is an effective antioxidant that can protect ovaries from oxidative damage. This study aims to systematically summarize and analyze the scientific literatures on glucose metabolism index, lipid profiles, inflammatory factor, and sex hormone level of PCOS patients treated with CoQ10 to provide a reference basis for clinical treatment., Methods: We will retrieve the following electronic databases from the built-in until March 2021: Cochrane Library, PubMed, EMBASE, Web of Science, China National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature Database (CBM), Clinical Trials. gov, Chinese Scientific Journal Database (VIP), and Wang-fang database. Two reviewers will independently scan the articles searched, de-duplication, filtering, quality assessment. Differences will be resolved by discussion between the 2 reviewers or by a third reviewers. All analyses were systematic to evaluate interventions based on the Cochrane handbook. Meta-analysis and/or subgroup analysis will be performed on the basis of the included studies., Discussion: This review will be to investigate the efficacy of CoQ10 supplementation on glucose metabolism, lipid profiles, and biomarkers of inflammation in women with PCOS and provide a high-quality synthesis to assess whether CoQ10 is an effective and safe intervention for PCOS. The results of the analysis will be published in a scientific journal after peer-review., Systematic Review Registration: INPLASY 2020100013.

Mitochondrial dysfunction has been repeatedly identified to be hallmark brain pathology underlying neuronal stress in Alzheimer's disease. As a result, mitochondrial medicine for the treatment of Alzheimer's disease has received increasing recognition. Idebenone (IDB) is a synthetic analog of Coenzyme Q10 (CoQ10) carrying antioxidizing property. Previous clinical trials reported a conflicting disease-modifying effect of IDB on Alzheimer's disease patients. However, whether IDB is preventive against amyloid beta (Aβ)-induced mitochondrial and neuronal stress has not been comprehensively investigated. In this study, we adopted an in-vitro setting by using primary cultured cortical neurons for the test. Neurons were pretreated with IDB prior to Aβ exposure. IDB pretreatment significant prevented neurons from Aβ-induced collapse of mitochondrial bioenergetics and perturbations of the protein kinase A (PKA)/cAMP response element-binding protein (CREB) signaling. Importantly, the treatment of IDB alone demonstrated an indiscernible side effect on the measured mitochondrial function, PKA/CREB signaling and neuronal viability. Therefore, our findings in together show a preventive effect of IDB against Aβ-mediated mitochondrial and neuronal injury. The use of IDB may hold potential to reduce the risk of Alzheimer's disease as a preventive strategy.

Purpose: To determine whether ubiquinol improves mitochondrial function and cell viability in human donor corneal endothelial cells during hypothermic corneal tissue storage., Methods: Endothelial cell Descemet membrane tissues were treated with 10 μM ubiquinol, the reduced form of the antioxidant coenzyme Q10, for 5 days in Optisol-GS storage media before assaying for mitochondrial activity using extracellular flux analysis of oxygen consumption. In addition, endothelial cell Descemet membrane tissues were analyzed for cell viability using apoptosis and necrosis assays. Control tissues from mate corneas were treated with diluent only, and comparisons were analyzed for differences., Results: A total of 13 donor corneal tissues with a mean (SEM) preservation time of 11.8 days (0.4) were included for the analysis. Treatment with 10 μM ubiquinol increased spare respiratory capacity by 174% (P = 0.001), maximal respiration by 93% (P = 0.003), and proton leak by 80% (P = 0.047) compared with controls. Cells treated with ubiquinol had no significant change in cell necrosis or apoptosis., Conclusions: Preliminary testing in donor corneal tissue at specified doses indicates that ubiquinol may be a useful biocompatible additive to hypothermic corneal storage media that increases corneal endothelial cell mitochondrial function. Additional investigations are indicated to further study and optimize the dose and formulation of ubiquinol for use in preserving donor corneal tissue function during hypothermic storage.

Purpose: Renal ischemia-reperfusion injury (RIRI) may occur secondary to several reasons leading to renal failure. Coenzyme-Q10 (CoQ10) is a well-known antioxidant. However, the effects CoQ10 against RIRI have not been evaluated. Our aim was to evaluate protective effects of CoQ10 to renal ischemia-reperfusion by biochemical, immunohistochemical and scintigraphic findings., Methods: Thirty Wistar-albino rats were randomly separated into groups of 10; Group Sham; Group ischemia-reperfusion (IR) had left renal pedicle clamping; Group CoQ10+IR had IR and CoQ10. Twenty-four hours later after reperfusion, scintigraphy was performed and after that, rats were sacrificed. To demonstrate effects of RIRI, serum urea and creatinine levels and tissue levels oxidative stress markers were evaluated. Both kidneys were subjected to histopathological evaluation and to confirm RIRI-induced immunohistochemical aspects of apoptosis, terminal-deoxynucleotidyl-transferase mediated-deoxyuridine-triphosphate-nick-end-labeling assay and caspase-3 were assessed., Results: Tissue oxidative stress, histopathologic changes, apoptosis scores and quantitative scintigraphic parameters were significantly higher in Group IR compared with Group Sham. Although tissue oxidative stress levels and histopathologic changes were not significant, quantitative scintigraphic parameters of contralateral kidney of Group IR were significantly increased. Compared with Group IR, Group CoQ10+IR presented decreased tissue oxidative stress levels; decreased scores of histopathology and apoptosis; and decreased quantitative scintigraphic parameters with increased split renal function in ischemic kidney., Conclusions: Our results suggest that other than its antioxidant properties, CoQ10 shows antiperoxidative, antiapoptotic and antiinflammatory potential in protecting renal functioning of ischemic kidney. Furthermore, our results show that renal scintigraphy is a feasible method to detect early changes in renal functioning after RIRI.

Background: The diabetic kidney disease (DKD) has become a seriously kidney disease that commonly caused by diabetes mellitus (DM). Oxidative stress response plays an essential role in the genesis and worsening of DKD and Coenzyme Q10 (CoQ10) has been reported the promising clinical effectiveness on DKD treatment. However, there is lack of relative evidence-based medical evidence currently., Objective: The systematic review and meta-analysis was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, which conducted to evaluate the effectiveness of CoQ10 in combination with other western medicine for DKD therapy through the randomized controlled trials (RCTs) and experimental studies., Methods: RCTs and experimental studies were searched based on standardized searching rules in 12 medical databases from the inception up to June 2018 and a total of 8 articles (4 RCTs and 4 experimental studies) were enrolled in the meta-analysis., Results: The results revealed that CoQ10 combined with other western medicine show statistical differences in the laboratory parameters of fasting plasma glucose (FPG), Hemoglobin A1c (HbA1c), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), triglyceride (TG), and malondialdehyde (MDA) amelioration after DKD therapy compared with control group. However, LDL-C and Urea level for RCTs and Urine output and Glucose for experimental studies on DKD was not superior to control group., Conclusion: We need to make conclusion cautiously for the effectiveness of CoQ10 application on DKD therapy. More standard, multicenter, double-blind RCTs, and formal experimental studies of CoQ10 treatment for DKD were urgent to be conducted for more clinical evidence providing in the future. The underlying pharmacological mechanism of CoQ10 needs to be researched and revealed for its future application on DKD therapy.

Objective: Most suicidality literature in Huntington disease (HD) is based on natural history studies or retrospective reviews, but reports on risk factors from clinical trials are limited., Methods: We analyzed 609 participants from 2CARE, a randomized, double-blind, placebo-controlled clinical trial with up to 5 years of follow-up, for risk factors related to suicidality. The primary outcome variable was the time from randomization until the first occurrence of either suicidal ideation or attempt. We also considered time from randomization until the first suicide attempt as a secondary outcome variable., Results: Depression, anxiety, bipolar disorder, antidepressant or anxiolytic use, and prior suicide attempt at baseline were associated with time to ideation or attempt. Baseline employment status, marital status, CAG repeat length, tetrabenazine use, and treatment assignment (coenzyme Q 10 or placebo) were not associated with suicidality. Time-dependent variables from the Unified Huntington's Disease Rating Scale Behavioral Assessment were associated with time to suicidal ideation or attempt, driven mainly by items related to depressed mood, low self-esteem/guilt, anxiety, suicidal thoughts, irritability, and compulsions. Variables associated with time to suicide attempt alone were generally similar., Conclusion: These data suggest psychiatric comorbidities in HD are predictive of suicidal behavior while participating in clinical trials, reinforcing the importance of clinical surveillance and treatment towards lessening risk during participation and perhaps beyond. Designing a composite algorithm for early prediction of suicide attempts in HD may be of value, particularly given anticipated trials aimed at disease modification are likely to be long-term., Clinicaltrialsgov Identifier: NCT00608881., (© 2019 American Academy of Neurology.)

Background and Purpose- Mitoquinone has been reported as a mitochondria-targeting antioxidant to promote mitophagy in various chronic diseases. Here, our aim was to study the role of mitoquinone in mitophagy activation and oxidative stress-induced neuronal death reduction after subarachnoid hemorrhage (SAH) in rats. Methods- Endovascular perforation was used for SAH model of male Sprague-Dawley rats. Exogenous mitoquinone was injected intraperitoneally 1 hour after SAH. ML385, an inhibitor of Nrf2 (nuclear factor-E2-related factor 2), was given intracerebroventricularly 24 hours before SAH. Small interfering RNA for PHB2 (prohibitin 2) was injected intracerebroventricularly 48 hours before SAH. Nuclear, mitochondrial, and cytoplasmic fractions were gathered using nucleus and mitochondria isolation kits. SAH grade evaluation, short- and long- term neurological function tests, oxidative stress, and apoptosis measurements were performed. Pathway related proteins were investigated with Western blot and immunofluorescence staining. Results- Expression of Keap1 (Kelch-like epichlorohydrin-associated protein 1, 2.84× at 24 hours), Nrf2 (2.78× at 3 hours), and LC3II (light chain 3-II; 1.94× at 24 hours) increased, whereas PHB2 (0.46× at 24 hours) decreased after SAH compared with sham group. Mitoquinone treatment attenuated oxidative stress and neuronal death, both short-term and long-term. Administration of mitoquinone resulted in a decrease in expression of Keap1 (0.33×), Romo1 (reactive oxygen species modulator 1; 0.24×), Bax (B-cell lymphoma-2 associated X protein; 0.31×), Cleaved Caspase-3 (0.29×) and an increase in Nrf2 (2.13×), Bcl-xl (B-cell lymphoma-extra large; 1.67×), PINK1 (phosphatase and tensin-induced kinase 1; 1.67×), Parkin (1.49×), PHB2 (1.60×), and LC3II (1.67×) proteins compared with SAH+vehicle group. ML385 abolished the treatment effects of mitoquinone on behavior and protein levels. PHB2 small interfering RNA reversed the outcomes of mitoquinone administration through reduction in protein expressions downstream of PHB2. Conclusions- Mitoquinone inhibited oxidative stress-related neuronal death by activating mitophagy via Keap1/Nrf2/PHB2 pathway after SAH. Mitoquinone may serve as a potential treatment to relieve brain injury after SAH.

Rationale: Mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) are thought to be rarely accompanied by macroangiopathy. We reported a case of MELAS that presented right distal internal carotid arterial (ICA) stenosis and reviewed 12 similar previously reported cases involving intracranial large blood vessels., Patient Concerns: A 38-year-old man suffered from recurrent stroke-like episodes (SE) such as alternating hemiparesis (right lesion 3 years ago and current left lesion), cortical blindness and seizure for 3 years, and was previously misdiagnosed as cerebral infarction. Magnetic Resonance Angiography (MRA) and Digital Subtraction Angiography (DSA) revealed right distal ICA stenosis and sparse cortex blood vessels, which were related to the previous SE., Diagnoses: He was diagnosed by genetic screening (a mitochondrial DNA A3243G point mutation) and presence of high lactic acidosis (4.03 mmol/L), which rose to 7.8 mmol/L after exercise., Intervention: The patient received Coenzyme Q10, vitamin C, L-arginine for 2 weeks and valproic acid sodium (400 mg bid) to prevent seizures till now., Outcomes: He is currently less active and intelligent than his peers, with occasional seizures, and needs family care., Lessons: Till date, there are 12 reported cases of MELAS combined with major cerebral arteries abnormalities including stenosis, dissection, occlusion, reversible vasoconstriction, aneurysms, and atherosclerosis. Hence, macroangiopathy in MELAS is not very rare. There is correlation between the affected vessels and the lesions in some cases, but not in others, which may increase the misdiagnosis rate. Hence, mitochondrial diseases cannot be excluded due to concurrent macroangiopathic lesions.

Rationale: Late-onset multiple acyl-coenzyme A dehydrogenase deficiency (MADD) mainly affects the neck extensor muscle group, which has been confirmed by novel mutations in electron-transferring-flavoprotein dehydrogenase (ETFDH). So far, a few cases have been reported with long-term follow-up. Here we report a case of late-onset MADD where the patient was followed up for 8 years during which time he underwent 2 muscle biopsies and 2 pathological examinations and his symptoms were significantly alleviated after appropriate treatments., Patient Concerns: In September 2009, a 16-year-old male patient was hospitalized due to gradually increasing difficulty in raising his head and weakness in limb muscles over a 6-month period. During the physical examination, the patient's neck extensor muscle strength was grade III-IV. His proximal limb muscle strength was grade IV, and his distal muscle strength was normal. His blood creatine kinase (CK) was 783 U/L., Diagnosis: Muscle biopsy revealed a large number of vacuolar fibers, which were mainly type I fibers. These findings were consistent with the diagnosis of lipid storage myopathy (LSM). ETFDH gene test detected C.736G > A at exon 7 and C.920C > G at exon 8., Interventions: Coenzyme Q10 treatment was administered. The first coenzyme Q10 40 mg tid was treated for three months, with the change of coenzyme Q10 20 mg tid for 6 months, followed by the change of coenzyme Q10 10 mg tid for long-term use., Outcomes: The patient's condition significantly improved after 3 months. At 7th year follow-up the patient's blood CK was normal, and a second muscle biopsy revealed no muscle vacuolar fibers and no increase in lipid droplets. Subsequently, the patient was withdrawn from the coenzyme Q10 treatment, and the condition of the patient remained normal., Lessons: Muscle biopsy was the main method used to determine LSM. Treatment with riboflavin should be started when the diagnosis of LSM is definitive. Furthermore, ETFDH gene tests should be performed for further classification. Moreover, coenzyme Q10 may be another effective drug for MADD.

Rationale: Dysferlin myopathy is an autosomal recessive hereditary muscular dystrophy due to deficiency of dysferlin caused by alteration of the DYSF gene; Limb-girdle muscular dystrophy type 2B (LGMD2B) is the most common in Its clinical phenotypes. However, LGMD2B is rarely seen in clinical cases and may initially present as weakness of proximalpelvis muscles and muscles in the posterior compartments of thighs,which will then cause difficulty in running and limping during walking. Laboratory tests at an early stage of the disease often indicate an increased level of serum creatine kinase (CK). Moreover, polymyositis (PM) is manifested as symmetrical proximal muscle weakness of the four limbs, accompanied by an increased level of serum CK. Thus, both are very difficult to identify in clinical practice., Patient Concerns: A 25-year-old woman was admitted to our department as the limb weakness progressively worsened. She began to experience proximal muscle weakness of both lower limbs without obvious inducement, which markedly increased when she climbed the stairs or stood up after squatting. Then her symptoms worsened, with difficulty in proximal and distal lifting of the lower extremities., Diagnoses: Through combined immunohistochemistry and Western-blot analysis, The patient was diagnosed with LGMD2B., Interventions: There were symptomatic treatments such as coenzyme Q10., Outcomes: After symptomatic treatments, the patient's symptoms were obviously relieved, and the CK level decreased., Lessons: Through this case, we found that combined application of immunohistochemistry and Western-blot analysis is helpful in early diagnosis of LGMD2B, and a new site of frame-shift mutation in the patient's DYSF gene was found.

Hypothesis: Mitoquinone (MitoQ) attenuates amikacin ototoxicity in guinea pigs., Background: MitoQ, a mitochondria-targeted derivative of the antioxidant ubiquinone, has improved bioavailability and demonstrated safety in humans. Thus, MitoQ is a promising therapeutic approach for protecting against amikacin-induced ototoxicity., Methods: Both oral and subcutaneous administrations of MitoQ were tested. Amikacin-treated guinea pigs (n = 12-18 per group) received water alone (control) or MitoQ 30 mg/l-supplemented drinking water; or injected subcutaneously with 3 to 5 mg/kg MitoQ or saline (control). Auditory brainstem responses and distortion product otoacoustic emissions were measured before MitoQ or control solution administration and after amikacin injections. Cochlear hair cell damage was assessed using scanning electron microscopy and Western blotting., Results: With oral administration, animals that received 30 mg/l MitoQ had better hearing than controls at only 24 kHz at 3-week (p = 0.017) and 6-week (p = 0.027) post-amikacin. With subcutaneous administration, MitoQ-injected guinea pigs had better hearing than controls at only 24 kHz, 2-week post-amikacin (p = 0.013). Distortion product otoacoustic emission (DPOAE) amplitudes were decreased after amikacin injections, but were not different between treatments (p > 0.05). Electron microscopy showed minor difference in outer hair cell loss between treatments. Western blotting demonstrated limited attenuation of oxidative stress in the cochlea of MitoQ-supplemented guinea pigs., Conclusions: Oral or subcutaneous MitoQ provided limited protection against amikacin-induced hearing loss and cochlear damage in guinea pigs. Other strategies for attenuating aminoglycoside-induced ototoxicity should be explored.

Objective: To identify an improved measure of clinical progression in early Huntington disease (HD) using data from prospective observational cohort studies and placebo group data from randomized double-blind clinical trials., Methods: We studied Unified Huntington Disease Rating Scale (UHDRS) and non-UHDRS clinical measures and brain measures of progressive atrophy in 1,668 individuals with early HD followed up prospectively for up to 30 to 36 months of longitudinal clinical follow-up., Results: The results demonstrated that a composite measure of motor, cognitive, and global functional decline best characterized clinical progression and was most strongly associated with brain measures of progressive corticostriatal atrophy., Conclusions: Use of a composite motor, cognitive, and global functional clinical outcome measure in HD provides an improved measure of clinical progression more related to measures of progressive brain atrophy and provides an opportunity for enhanced clinical trial efficiency relative to currently used individual motor, cognitive, and functional outcome measures., (© 2017 American Academy of Neurology.)

Leber hereditary optic neuropathy (LHON) is currently estimated as the most frequent mitochondrial disease (1 in 27,000-45,000). Its molecular pathogenesis and natural history is now fairly well understood. LHON also is the first mitochondrial disease for which a treatment has been approved (idebenone-Raxone, Santhera Pharmaceuticals) by the European Medicine Agency, under exceptional circumstances because of the rarity and severity of the disease. However, what remains unclear includes the optimal target population, timing, dose, and frequency of administration of idebenone in LHON due to lack of accepted definitions, criteria, and general guidelines for the clinical management of LHON. To address these issues, a consensus conference with a panel of experts from Europe and North America was held in Milan, Italy, in 2016. The intent was to provide expert consensus statements for the clinical and therapeutic management of LHON based on the currently available evidence. We report the conclusions of this conference, providing the guidelines for clinical and therapeutic management of LHON.

Rationale: Mitochondrial nephropathy has a poor prognosis and often progresses to the end-stage renal disease. Renal pathology often is focal segmental glomerulosclerosis (FSGS) and does not respond to steroid therapy or immunosuppressive therapy. Some patients are benefited from the therapy of coenzyme Q10, which affect the synthesis pathway of coenzyme Q10., Patient Concerns: Herein, we report 2 cases of children with proteinuria renal disease with ADCK4 mutation., Diagnoses: Proteinuria renal disease with ADCK4 mutation., Interventions: Compound heterozygous mutation in ADCK4 gene were detected with next-generation sequencing and confirmed by Sanger sequencing. Both of the patients were given coenzyme Q10 supplementation therapy., Outcomes: The first patient showed a decreased proteinuria after coenzyme Q10 supplementation therapy, while the other was not improved., Lessons: Based on the cases we reported and from the literature, recognition of ADCK4 mutation through early and accurate genetic screening could be helpful in avoiding unnecessary toxicities and in preventing complications arising in mitochondrial nephropathy., (Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Antiphospholipid syndrome (APS) leukocytes exhibit an oxidative perturbation, directly linked to alterations in mitochondrial dynamics and metabolism. This disturbance is related to the patients' prothrombotic status and can be prevented by in vitro treatment with coenzyme Q10. Our aim was to investigate short-term effects of in vivo ubiquinol (reduced coenzyme Q 10 [Q red ]) supplementation on markers related to inflammation and thrombosis in APS through a prospective, randomized, crossover, placebo-controlled trial., Approach and Results: Thirty-six patients with APS were randomized to receive Q red (200 mg/d) or placebo for 1 month. Thirty-three patients with APS completed the intervention, which increased plasma coenzyme Q 10 . Q red improved endothelial function and decreased monocyte expression of prothrombotic and proinflammatory mediators, inhibited phosphorylation of thrombosis-related protein kinases, and decreased peroxides and percentage of monocytes with depolarized mitochondria; mitochondrial size was increased, and mitochondrial biogenesis-related genes were upregulated. Q red ameliorated extruded neutrophil extracellular traps in neutrophils and downregulated peroxides, intracellular elastase, and myeloperoxidase. Nanostring microRNA profiling revealed 20 microRNAs reduced in APS monocytes, and 16 of them, with a preponderance of cardiovascular disease-related target mRNAs, were upregulated. Monocytes gene profiling showed differential expression of 29 atherosclerosis-related genes, 23 of them changed by Q red . Interaction networks of genes and microRNAs were identified. Correlation studies demonstrated co-ordinated effects of Q red on thrombosis and endothelial function-associated molecules., Conclusions: Our results highlight the potential of Q red to modulate the overexpression of inflammatory and thrombotic risk markers in APS. Because of the absence of clinically significant side effects and its potential therapeutic benefits, Q red might act as safe adjunct to standard therapies in APS., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02218476., (© 2017 American Heart Association, Inc.)

Purpose: The management of nonhealing corneal ulcers, particularly in patients with neurotrophic corneas, remains a challenging problem today. Some patients may fail to respond to conventional therapy, making new alternative agents necessary to treat these resistant cases. In this article, we aim to present six challenging cases of refractory corneal ulcers that revealed healing response to the adjuvant treatment with coenzyme Q10 (CoQ10) eye drops and to review the literature examining of new therapeutic agents., Methods: Our study was designed as a descriptive case series demonstrating the use of novel coenzyme Q10 eye drops in refractory corneal ulcers. In our case series, CoQ10 eye drops were added to the existing therapies as an adjuvant agent in six cases: three cases with neurotrophic corneal ulcers, two cases with postinfectious corneal ulcers (one unknown etiology+one Acanthamoeba keratitis), and 1 case with Stevens-Johnson syndrome. All cases were monitored regularly and corneal images were taken at all visits., Results: All nonhealing corneas with conventional therapy revealed recovery after the addition of CoQ10 eye drops. Except for two cases that responded to the CoQ10 eye drops more rapidly (within 1 to 2 weeks), complete corneal healing was observed in four cases between weeks 4 and 8. No adverse events were reported in these cases throughout the follow-up period., Conclusion: Coenzyme Q10 eye drops can be considered as an important adjuvant therapeutic agent promoting corneal epithelial wound healing in challenging cases.

Objective: To investigate mitophagy in 5 patients with severe dominantly inherited optic atrophy (DOA), caused by depletion of OPA1 (a protein that is essential for mitochondrial fusion), compared with healthy controls., Methods: Patients with severe DOA (DOA plus) had peripheral neuropathy, cognitive regression, and epilepsy in addition to loss of vision. We quantified mitophagy in dermal fibroblasts, using 2 high throughput imaging systems, by visualizing colocalization of mitochondrial fragments with engulfing autophagosomes., Results: Fibroblasts from 3 biallelic OPA1(-/-) patients with severe DOA had increased mitochondrial fragmentation and mitochondrial DNA (mtDNA)-depleted cells due to decreased levels of OPA1 protein. Similarly, in siRNA-treated control fibroblasts, profound OPA1 knockdown caused mitochondrial fragmentation, loss of mtDNA, impaired mitochondrial function, and mitochondrial mislocalization. Compared to controls, basal mitophagy (abundance of autophagosomes colocalizing with mitochondria) was increased in (1) biallelic patients, (2) monoallelic patients with DOA plus, and (3) OPA1 siRNA-treated control cultures. Mitophagic flux was also increased. Genetic knockdown of the mitophagy protein ATG7 confirmed this by eliminating differences between patient and control fibroblasts., Conclusions: We demonstrated increased mitophagy and excessive mitochondrial fragmentation in primary human cultures associated with DOA plus due to biallelic OPA1 mutations. We previously found that increased mitophagy (mitochondrial recycling) was associated with visual loss in another mitochondrial optic neuropathy, Leber hereditary optic neuropathy (LHON). Combined with our LHON findings, this implicates excessive mitochondrial fragmentation, dysregulated mitophagy, and impaired response to energetic stress in the pathogenesis of mitochondrial optic neuropathies, potentially linked with mitochondrial mislocalization and mtDNA depletion., (Copyright © 2016 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: To test the hypothesis that chronic treatment of early-stage Huntington disease (HD) with high-dose coenzyme Q10 (CoQ) will slow the progressive functional decline of HD., Methods: We performed a multicenter randomized, double-blind, placebo-controlled trial. Patients with early-stage HD (n = 609) were enrolled at 48 sites in the United States, Canada, and Australia from 2008 to 2012. Patients were randomized to receive either CoQ 2,400 mg/d or matching placebo, then followed for 60 months. The primary outcome variable was the change from baseline to month 60 in Total Functional Capacity score (for patients who survived) combined with time to death (for patients who died) analyzed using a joint-rank analysis approach., Results: An interim analysis for futility revealed a conditional power of <5% for the primary analysis, prompting premature conclusion in July 2014. No statistically significant differences were seen between treatment groups for the primary or secondary outcome measures. CoQ was generally safe and well-tolerated throughout the study., Conclusions: These data do not justify use of CoQ as a treatment to slow functional decline in HD., Clinicaltrialsgov Identifier: NCT00608881., Classification of Evidence: This article provides Class I evidence that CoQ does not slow the progressive functional decline of patients with HD., (© 2016 American Academy of Neurology.)

Coenzyme Q10 (CoQ10) supplementation has been shown to decrease oxidative stress in a number of clinical settings. However, there are mixed results regarding the role of CoQ10 supplementation on exercise performance. Chronic kidney disease is recognized as an inflammatory state, and hemodialysis patients have low level of exercise performance. We aimed to evaluate the effect of CoQ10 supplementation on oxidative stress markers and exercise performance measures. This was a prospective, double-blind, placebo-controlled, crossover study in which all patients received placebo and oral CoQ10 200 mg/d. Participants underwent 6-minute walking test and cycle ergometer. Blood samples were drawn to determine malondialdehyde, oxidized low-density lipoprotein, superoxide dismutase, and glutathione peroxidase. Walking distance in 6-minute walking test and estimated maximal oxygen consumption (VO2max) were recorded. Twenty-eight patients were randomized, but 23 patients completed the study protocol. Serum CoQ10 level significantly increased with supplementation compared with basal values (P < 0.05). Neither walking distance nor estimated VO2max was different between the placebo and CoQ10 groups (P > 0.05). Serum malondialdehyde levels significantly increased in both groups compared with baseline values just after the exercise (P < 0.05). There was no difference in markers of oxidative stress and antioxidant system between placebo and CoQ10 supplementation with exercise (P > 0.05). The results of this study showed no significant effect of CoQ10 supplementation on exercise performance measures and oxidative system markers compared with placebo in maintenance hemodialysis patients.

Purpose: Corneal involvement in mitochondrial disease is seldom described. Kearns-Sayre syndrome (KSS) is a mitochondrial disorder characterized by retinitis pigmentosa, external ophthalmoplegia, and heart block. We report 2 patients with KSS with corneal lesions involving the endothelium, which improved with Coenzyme Q10 (CoQ10). Based on recent research regarding the role of dysfunctional oxidative metabolism in Fuchs Endothelial Corneal Dystrophy (FECD), we propose that mitochondrial diseases and FECD share a final pathway., Methods: A chart review was performed and a review of the literature was completed with a PubMed search using the terms "Kearns-Sayre Syndrome", "mitochondria", "endothelium", "Fuchs endothelial corneal dystrophy", and "cornea"., Results: There are 19 reports of corneal involvement in clinical phenotypes of mitochondrial disease. Nine of these 19 cases had findings consistent with KSS. Our patients with KSS had microcystic changes throughout the cornea and excrescences on the endothelial surface seen with ultrasound biomicroscopy, similar to the clinical findings in FECD. CoQ10 improved corneal disease in both children. CoQ10 deficiency has been reported in a variety of mitochondrial diseases, and efficacy of supplementation has been demonstrated. It may be beneficial in these patients because of its antioxidant properties and role in oxidative phosphorylation., Conclusions: The common deletion found in patients with KSS has recently been implicated in FECD, which has recently been shown to be a disease related to dysfunctional oxidative metabolism. Future research should explore the use of antioxidants, such as CoQ10 in patients with FECD.

Background: Acute viral myocarditis is an inflammatory disease with global impact. Although it may resolve spontaneously, its course is not easily predicted, and there is a paucity of specific treatment options available with proven efficacy. Coenzyme Q10 (CQ10) and trimetazidine possess antioxidant and antiinflammatory effects., Methods: We examined the therapeutic efficacy of these agents in acute viral myocarditis both individually and in combination. Patients were blinded and randomized to receive CQ10 (n = 42), trimetazidine (n = 39), or CQ10 + trimetazidine (n = 43) treatment., Results: Serum inflammatory and oxidative stress marker and myocardial enzyme levels, and heart function were measured. Both CQ10 and trimetazidine decreased inflammatory and oxidative stress biomarker levels compared with baseline measurements. However, combination therapy with CQ10 and trimetazidine showed a significantly more powerful effect not only on markers of inflammation and oxidative stress, but also on left ventricular systolic function and troponin, compared with either treatment alone., Conclusion: This study confirmed the beneficial effect of CQ10 and trimetazidine individually, but demonstrated a superior effect of combining the therapies on cardiac left ventricular ejection fraction, and biochemical markers of myocardial damage in acute viral myocarditis.

Exogenous administration of coenzyme Q10 (CoQ10) has been shown in experimental models to have a protective effect against ischemia-reperfusion injury. However, it is unclear whether follow-up plasma CoQ10 concentration is prognostic of left ventricular (LV) performance after primary balloon angioplasty in patients with acute ST segment elevation myocardial infarction (STEMI).We prospectively recruited 55 patients with STEMI who were treated with primary coronary balloon angioplasty. Plasma CoQ10 concentrations were measured before primary angioplasty (baseline) and 3 days, 7 days, and 1 month after STEMI using high-performance liquid chromatography. Echocardiography was performed at baseline and at 6-month follow-up. The control group comprised 54 healthy age- and sex-matched volunteers.Serial circulating CoQ10 concentrations significantly decreased with time in the STEMI group. The LV ejection fraction at 6-month follow-up positively correlated with the 1-month plasma CoQ10 tertile. Higher plasma CoQ10 concentrations at 1 month were associated with favorable LV remodeling and systolic function 6 months after STEMI. Multiple linear regression analysis showed that changes in CoQ10 concentrations at 1-month follow-up were predictive of LV systolic function 6 months after STEMI. Changes in CoQ10 concentrations correlated negatively with baseline oxidized low-density lipoprotein and fibrinogen concentrations and correlated positively with leukocyte mitochondrial copy number at baseline.Patients with STEMI who had higher plasma CoQ10 concentrations 1 month after primary angioplasty had better LV performance at 6-month follow-up. In addition, higher plasma CoQ10 concentration was associated with lower grade inflammatory and oxidative stress status. Therefore, plasma CoQ10 concentration may serve as a novel prognostic biomarker of LV systolic function after revascularization therapy for acute myocardial infarction.

Heart failure (HF) with either preserved or reduced ejection fraction is associated with increased morbidity and mortality. Evidence-based therapies are often limited by tolerability, hypotension, electrolyte disturbances, and renal dysfunction. Coenzyme Q10 (CoQ10) may represent a safe therapeutic option for patients with HF. CoQ10 is a highly lipophilic molecule with a chemical structure similar to vitamin K. Although being a common component of cellular membranes, CoQ10's most prominent role is to facilitate the production of adenosine triphosphate in the mitochondria by participating in redox reactions within the electron transport chain. Numerous trials during the past 30 years examining CoQ10 in patients with HF have been limited by small numbers and lack of contemporary HF therapies. The recent publication of the Q-SYMBIO randomized controlled trial demonstrated a reduction in major adverse cardiovascular events with CoQ10 supplementation in a contemporary HF population. Although having limitations, this study has renewed interest in evaluating CoQ10 supplementation in patients with HF. Current literature suggests that CoQ10 is relatively safe with few drug interactions and side effects. Furthermore, it is already widely available as an over-the-counter supplement. These findings warrant future adequately powered randomized controlled trials of CoQ10 supplementation in patients with HF. This state-of-the-art review summarizes the literature about the mechanisms, clinical data, and safety profile of CoQ10 supplementation in patients with HF., (© 2016 American Heart Association, Inc.)

Coenzyme Q10 (CoQ10) crosses the blood-brain barrier when administered intravenously and accumulates in the brain. In this study, we investigated whether CoQ10 protects against ischemia-reperfusion injury by measuring neurological function and brain infarct volumes in a rat model of transient focal cerebral ischemia. In male Wistar rats, we performed transient middle cerebral artery occlusion (tMCAO) for 60 minutes, followed by reperfusion for 24 hours or 7 days. Forty-five minutes after the onset of occlusion (or 15 minutes before reperfusion), rats received a single intravenous injection of solubilized CoQ10 (30 mg·mL(-1)·kg(-1)) or saline (2 mL/kg). Sensory and motor function scores and body weights were obtained before the rats were killed by decapitation, and brain infarct volumes were calculated using tetrazolium chloride staining. CoQ10 brain levels were measured by high-performance liquid chromatography with electrochemical detection. CoQ10 significantly improved neurological behavior and reduced weight loss up to 7 days after tMCAO (P < 0.05). Furthermore, CoQ10 reduced cerebral infarct volumes by 67% at 24 hours after tMCAO and 35% at 7 days (P < 0.05). Cerebral ischemia resulted in a significant reduction in endogenous CoQ10 in both hemispheres (P < 0.05). However, intravenous injection of solubilized CoQ10 resulted in its increase in both hemispheres at 24 hours and in the contralateral hemisphere at 7 days (P < 0.05). Our results demonstrate that CoQ10 is a robust neuroprotective agent against ischemia-reperfusion brain injury in rats, improving both functional and morphological indices of brain damage.

Purpose of Review: To discuss recent advances in potential treatments for Leber hereditary optic neuropathy (LHON), a typically visually devastating hereditary optic neuropathy caused by mutations in the mitochondrial genome., Recent Findings: Idebenone has been proposed as a means of bypassing defective complex I activity and a free radical scavenger to prevent oxidative damage. EPI-743 may have more potency than idebenone, but no clinical trials have been performed. Gene therapy techniques have advanced significantly, including allotopic expression and nuclear transfer. Successful rescue of animal models of LHON with both of these therapies has been demonstrated. Introduction of exogenous DNA into the mitochondrial genome with mitochondrial targeting of viral vectors is another promising technique., Summary: There are currently no proven treatments for LHON. However, there are many promising novel treatment modalities that are currently being evaluated, with several clinical trials underway or in the planning stages. Supportive measures and genetic counseling remain of great importance for these patients.

Hypothesis: Mitoquinone (MitoQ) attenuates aminoglycoside (AG)-induced upregulation of the proapoptotic molecules Bak and harakiri (Hrk) and decreases the percentage of apoptotic House Ear Institute Organ of Corti 1 (HEI-OC1) cells., Background: The primary mechanism of AG ototoxicity is the formation of reactive oxygen species, which leads to hair cell death via apoptotic and nonapoptotic pathways. Antioxidants have been shown to protect against AG ototoxicity. Mitoquinone is a mitochondria-targeted derivative of the antioxidant ubiquinone. Thus, MitoQ may be more effective in preventing AG ototoxicity compared with untargeted antioxidants., Methods: Ribonucleic acid from untreated HEI-OC1 cells and cells exposed to gentamicin with and without preincubation with MitoQ, idebenone (IDB, an untargeted ubiquinone), or decylTPP (positive control) were used to assess gene expression of Bak and Hrk using real-time polymerase chain reaction. Protein expression of Bak and Hrk was determined by Western blotting. Annexin V assay using flow cytometry was performed to assess the percentage of apoptotic HEI-OC1 cells treated with gentamicin with and without preincubation with MitoQ, decylTPP, or IDB., Results: Preincubation of HEI-OC1 cells with MitoQ significantly decreased the gentamicin-induced upregulation of Bak gene (p = 0.03) but not preincubation with IDB (p = 0.87). Harakiri levels were very low that relative quantification could not be carried out. Protein levels of Bak and Hrk were not different between treatments. Annexin V assay showed that gentamicin increased the percentage of apoptotic cells (p < 0.05) compared with control. However, the percentages of apoptotic cells in gentamicin-treated and cells pretreated with the antioxidants MitoQ or IDB were not different., Conclusion: Mitoquinone attenuated the gentamicin-induced upregulation of the Bak gene but not its product, the proapoptotic molecule Bak, and MitoQ did not significantly decrease the gentamicin-induced cell apoptosis in vitro. Further in vivo studies are needed to assess the clinical significance of these findings.

Previous studies of Japanese migrants have suggested that the increase in colorectal cancer rates occurring after migration is slower among Japanese Brazilians than among Japanese Americans. We hypothesized that this difference may partly reflect differences in vegetable and fruit intake between the populations. Using data from validation studies of food frequency questionnaires being used in comparative case-control studies of colorectal adenoma in Tokyo, São Paulo, and Hawaii, plasma carotenoid, retinol, tocopherol, and coenzyme Q10 levels were measured by high-performance liquid chromatography, and 25-hydroxy vitamin D levels were estimated by enzyme-linked immunosorbent assay. Plasma levels were compared by analysis of covariance between 142 Japanese in Tokyo, 79 Japanese Brazilians in São Paulo, and 78 Japanese Americans in Hawaii. Overall, we found significantly lower plasma carotenoid levels, except for lycopene levels, and retinol levels in Japanese Americans compared with Japanese in Tokyo and Japanese Brazilians. The plasma total carotenoid level was highest in Japanese Brazilians. Compared with the mean level among Japanese Brazilians (1741.2 ng/ml), P for difference was 0.03 among Japanese in Tokyo (1514.4 ng/ml) and less than 0.01 for Japanese Americans (1257.7 ng/ml). Plasma lycopene and tocopherol levels did not substantially differ between the three populations. We also found significantly lower plasma levels of 25-hydroxy vitamin D and total coenzyme Q10 in Japanese in Tokyo than in Japanese Americans and Japanese Brazilians. Higher levels of plasma carotenoids among Japanese Brazilians than among Japanese in Tokyo and Hawaii may have contributed to the slower pace of the increase in colorectal cancer rates observed in that population after migration.

Background: The mechanisms of general anesthesia by volatile drugs remain largely unknown. Mitochondrial dysfunction and reduction in energy levels have been suggested to be associated with general anesthesia status. 2-Deoxy-D-glucose (2-DG), an analog of glucose, inhibits hexokinase and reduces cellular levels of adenosine triphosphate (ATP). 3-Nitropropionic acid is another compound which can deplete ATP levels. In contrast, idebenone and L-carnitine could rescue deficits of energy. We therefore sought to determine whether 2-DG and/or 3-nitropropionic acid can enhance the anesthetic effects of isoflurane, and whether idebenone and L-carnitine can reverse the actions of 2-DG., Methods: C57BL/6J mice (8 months old) received different concentrations of isoflurane with and without the treatments of 2-DG, 3-nitropropionic acid, idebenone, and L-carnitine. Isoflurane-induced loss of righting reflex (LORR) was determined in the mice. ATP levels in H4 human neuroglioma cells were assessed after these treatments. Finally, 31P-magnetic resonance spectroscopy was used to determine the effects of isoflurane on brain ATP levels in the mice., Results: 2-DG enhanced isoflurane-induced LORR (P = 0.002, N = 15). 3-Nitropropionic acid also enhanced the anesthetic effects of isoflurane (P = 0.005, N = 15). Idebenone (idebenone + saline versus idebenone + 2-DG: P = 0.165, N = 15), but not L-carnitine (L-carnitine + saline versus L-carnitine + 2-DG: P < 0.0001, N = 15), inhibited the effects of 2-DG on enhancing isoflurane-induced LORR in the mice, as evidenced by 2-DG not enhancing isoflurane-induced LORR in the mice pretreated with idebenone. Idebenone (idebenone + saline versus idebenone + 2-DG: P = 0.177, N = 6), but not L-carnitine (L-carnitine + saline versus L-carnitine + 2-DG: P = 0.029, N = 6), also mitigated the effects of 2-DG on reducing ATP levels in cells, as evidenced by 2-DG not decreasing ATP levels in the cells pretreated with idebenone. Finally, isoflurane decreased ATP levels in both cultured cells and mouse brains (β-ATP: P = 0.003, N = 10; β-ATP/phosphocreatine: P = 0.006, N = 10; β-ATP/inorganic phosphate: P = 0.001, N = 10)., Conclusions: These results from our pilot studies have established a system and generated a hypothesis that 2-DG enhances anesthetic effects via reducing energy levels. These findings should promote further studies to investigate anesthesia mechanisms.

Objective: The aim of this study is to show the possible positive effect of coenzyme Q10 (Co Q10) on regenerating in facial palsy., Materials and Methods: Sixteen female Sprague-Dawley albino rats were randomly divided into 2 groups as Co Q10 and control groups. Group Q10 (n = 8) received Co Q10 of 10 mg/kg/d intraperitoneally for 30 days, and group C (n = 8) received saline solution of 1 mL/d intraperitoneally once daily for 30 days. The right facial nerve stimulation thresholds were determined before crush, immediately after crush, and after 1 month.After determination of the thresholds, the crushed part of the facial nerve was then excised. All specimens were examined by a pathologist using a light microscope., Results: No statistically significant difference in stimulation threshold was found between the Co Q10 and saline groups after crushing (P = 0.645). After 1 month of treatment, stimulation thresholds were significantly lower in both the Co Q10 and saline groups (Ps = 0.028 and 0.016). However, the Co Q10 group showed greater improvement than the saline group (P = 0.050).After 1 month of treatment, neither the Co Q10 group nor the saline group had reached the precrushing amplitude levels (Ps = 0.027 and 0.011).Significant differences were found in vascular congestion, macrovacuolization, and myelin thickness between the Co Q10 and control groups by light microscopy (P < 0.05)., Conclusions: Although many treatment methods have been tried to accelerate facial nerve regeneration after trauma, a definitive method has not been found yet. Co Q for the treatment of acute facial paralysis is promising on both physiologic assessments and pathologic evaluation.

Objective: Recent studies have shown the role of miRNAs in macrophage reverse cholesterol transport and atherogenesis. We hypothesized that coenzyme Q10 (CoQ10) may increase macrophage reverse cholesterol transport by regulating miRNA expression that contributes to the prevention of atherosclerosis., Approach and Results: CoQ10 treatment suppressed oxidized low-density lipoprotein-induced macrophage foam cell formation by ameliorating the binding of activator protein-1 to the putative promoter region of miR-378 primary transcript, thus decreasing the miR-378 level and enhancing the ATP-binding cassette transporter G1-mediated macrophage cholesterol efflux to high-density lipoprotein. Subsequently, the axis of activator protein-1/miR-378/ATP-binding cassette transporter G1 cholesterol efflux was confirmed in peritoneal macrophages isolated from CoQ10-treated apolipoprotein E-deficient mice. Finally, CoQ10 consumption promoted macrophage reverse cholesterol transport and inhibited the progression of atherosclerosis in apolipoprotein E-deficient mice., Conclusions: This study identified activator protein-1/miR-378/ATP-binding cassette transporter G1 as a novel cascade for CoQ10 in facilitating macrophage cholesterol efflux in vitro and in vivo. Our data thus imply that both CoQ10 and miR-378 are promising candidates for atherosclerosis prevention and treatment., (© 2014 American Heart Association, Inc.)

Hypothesis: Oral supplementation with mitoquinone (MitoQ) prevents gentamicin-induced ototoxicity in guinea pigs., Background: Antioxidants have been shown to protect against aminoglycoside (AG)-induced ototoxicity. MitoQ, a mitochondria-targeted derivative of the antioxidant ubiquinone, is attached to a lipophilic triphenylphosphonium (TPP) cation, which enables its accumulation inside the mitochondria several hundred-fold over the untargeted antioxidant. MitoQ has improved bioavailability and can reach most tissues and has been used in Parkinson's disease and hepatitis C human trials, which demonstrated that MitoQ can be safely used in humans. Thus, MitoQ is a promising novel therapeutic approach for protecting against AG-induced ototoxicity., Methods: Gentamicin-treated guinea pigs were supplied with water alone (control), decyl-TPP (positive control), or MitoQ-supplemented drinking water. Auditory function was assessed by auditory brainstem response. Cochlear damage was assessed using scanning electron microscopy. Western blotting was performed to evaluate changes in proteins related to apoptosis and oxidative damage in the cochlea., Results: Threshold shifts at 4 and 8 kHz at 4 and 7 weeks after gentamicin treatment were smaller in animals treated with MitoQ compared with those in the control- and decyl-TPP-treated animals (p < 0.05). Protein carbonyls and levels of the proapoptotic protein Bak were lower (p < 0.05 and p = 0.008, respectively), whereas the level of the antioxidant enzyme manganese superoxide dismutase was higher (p = 0.01) in the cochlea of MitoQ-treated animals. The expression of 3-nitrotyrosine and Hrk were not different between groups (p > 0.05)., Conclusion: Oral supplementation with MitoQ attenuated gentamicin-induced cochlear damage and hearing loss in guinea pigs. MitoQ holds promise as a means for protecting against AG ototoxicity.

Background: Oxidative stress is a key factor implicated in the development of diabetic neuropathy. This study evaluates the prophylactic and antinociceptive effects of the antioxidant coenzyme Q10 (CoQ10) on diabetes-induced neuropathic pain in a diabetic mouse model., Methods: Total 56 mice with type 1 diabetes induced by streptozotocin were used, 20 normal mice were used as control. Mechanical and thermal nociceptive behavioral assays were applied to evaluate diabetic neuropathic pain. Tissue lipid peroxidation, immunohistochemistry, reverse transcription, and polymerase chain reaction were used to evaluate the molecular mechanisms of CoQ10. Data are presented as mean ± SEM., Results: CoQ10 administration was associated with reduced loss of body weight compared with nontreated diabetic mice, without affecting blood glucose levels. Low dose and long-term administration of CoQ10 prevented the development of neuropathic pain. Treatment with CoQ10 produced a significant dose-dependent inhibition of mechanical allodynia and thermal hyperalgesia in diabetic mice. Dorsal root ganglia, sciatic nerve, and spinal cord tissues from diabetic mice demonstrated increased lipid peroxidation that was reduced by CoQ10 treatment. CoQ10 administration was also noted to reduce the proinflammatory factors in the peripheral and central nervous system., Conclusions: The results of this study support the hypothesis that hyperglycemia induced neuronal oxidative damage and reactive inflammation may be pathogenic in diabetic neuropathic pain. CoQ10 may be protective by inhibiting oxidative stress and reducing inflammation by down-regulating proinflammatory factors. These results suggest that CoQ10 administration may represent a low-risk, high-reward strategy for preventing or treating diabetic neuropathy.

Background: The authors investigated the correlation of protan and tritan color vision with disease characteristics in Leber hereditary optic neuropathy (LHON). The authors also characterized the therapeutic potential of idebenone in protecting patients from developing dyschromatopsia in LHON., Methods: Color contrast data of 39 LHON patients participating in a randomized, double-blind placebo-controlled intervention study were evaluated. Patients reported disease onset <5 years before enrolment and were genetically confirmed. Protan and tritan color contrast sensitivity was measured using a computer graphics method in patients receiving idebenone (Catena; 900 mg/d; N = 28) or placebo (N = 11) for 6 months., Results: Mean age of patients was 28.1 years, 87.2% were men, 76.9% carried the m11778G>A mutation, and mean duration since onset was 2 years. Assessing protan and tritan color vision at baseline revealed a high degree of color confusion even in young patients (<25 years) and with a short history of disease (<1 year). Treatment with idebenone improved tritan color vision compared with placebo (P = 0.008 at week 24); a similar trend was seen for protan. The effect of idebenone was most prominent in patients with discordant visual acuity (interocular difference of logMAR >0.2). In this subgroup, the treatment effect at week 24 was 20.4% (P = 0.005) in favor of idebenone for the tritan color domain and 13.5% (P = 0.067) for the protan domain., Conclusion: This study confirms that protan and tritan color confusion is an early symptom in LHON. Treatment with idebenone can protect from loss of color vision, particularly in patients who are at imminent risk of further vision loss.

A 31-year-old woman developed subacute bilateral visual loss over a 2-week period. Two months later, the diagnosis of Leber hereditary optic neuropathy (LHON) 11778/ND4 was established and the patient was treated with 900 mg of idebenone daily. Over the ensuing 9 months, visual acuity improved from 20/200 to 20/25 in each eye with near-total resolution in visual field abnormalities. Our case report is in agreement with 2 large published series of patients with LHON treated with idebenone, raising hope for treatment of this visually devastating mitochondrial disorder.

This study investigated the neuroprotective effects of coenzyme Q10 (CoQ10) against oxidative stress induced by kainic acid (KA) in organotypic hippocampal slice culture of rats. Cultured slices were injured by exposure to 5 µM of KA for 18 h and then treated with different concentrations of CoQ10. Neuronal cell death measured as propidium iodide uptake was reduced at 24 h after treatment with 1 µM of CoQ10. We also observed an increased number of surviving CA3 neurons in 0.1 and 1 µM concentrations of CoQ10-treated groups using cresyl violet staining. CoQ10 (0.01, 0.1, and 1 µM) treatment significantly decreased the 2',7'-dichlorofluorescein fluorescence and the expression of NQO1 in the CoQ10-treated groups was significantly lower than that in the KA-only group. These results suggest that CoQ10 may protect hippocampal neurons against oxidative stress.

Purpose of Review: Treatment options for mitochondrial myopathies remain limited despite rapid advances in the understanding of the molecular basis of these conditions. Existing therapies continue to be evaluated and novel treatment strategies are starting to appear on the horizon., Recent Findings: Exercise training continues to show promise as a method of improving exercise tolerance and enhancing oxidative capacity. Coenzyme Q10 deficiency appears to be a relatively common finding in mitochondrial disorders and is likely to benefit from exogenous supplementation. Large-scale randomized clinical trials to evaluate these treatment options are now underway and this represents one of the most important developments in recent years. Activation of the peroxisome proliferator-activated receptor/peroxisome proliferator-activated receptor-gamma coactivator-1alpha pathway has been shown to induce mitochondrial biogenesis leading to a delayed onset of myopathy and prolonged lifespan in mouse models. A ketogenic diet has also been found to induce mitochondrial biogenesis in mice with mitochondrial myopathy., Summary: Therapeutic trials of exercise training and coenzyme Q10 supplementation should continue to be offered to patients with mitochondrial myopathies pending the results of evaluation in randomized clinical trials. Further investigation of peroxisome proliferator-activated receptor/peroxisome proliferator-activated receptor-gamma coactivator-1alpha pathway activation, ketogenic diets and other new strategies is required.