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Over the last decade, a number of distinct mutations in the mtDNA (mitochondrial DNA) have been found to be associated with both syndromic and non-syndromic forms of hearing impairment. Their real incidence as a cause of deafness is poorly understood and generally underestimated. Among the known mtDNA mutations, the A1555G mutation in the 12S gene has been identified to be one of the most common genetic cause of deafness, and it has been described to be both associated to non-syndromic progressive SNHL (sensorineural hearing loss) and to aminoglycoside-induced SNHL. In the present study, we have investigated the presence of mtDNA alterations in patients affected by idiopathic non-syndromic SNHL, both familiar and sporadic, in order to evaluate the frequency of mtDNA alterations as a cause of deafness and to describe the audiological manifestations of mitochondrial non-syndromic SNHL. In agreement with previous studies, we found the A1555G mutation to be responsible for a relevant percentage (5.4%) of cases affected with isolated idiopathic sensorineural hearing impairment.

During aging, brain performances decline. Cellular senescence is one of the aging drivers and a key feature of a variety of human age‐related disorders. The transcriptional repressor RE1‐silencing transcription factor (REST) has been associated with aging and higher risk of neurodegenerative disorders. However, how REST contributes to the senescence program and functional impairment remains largely unknown. Here, we report that REST is essential to prevent the senescence phenotype in primary mouse neurons. REST deficiency causes failure of autophagy and loss of proteostasis, increased oxidative stress, and higher rate of cell death. Re‐establishment of autophagy reverses the main hallmarks of senescence. Our data indicate that REST has a protective role in physiological aging by regulating the autophagic flux and the senescence program in neurons, with implications for neurological disorders associated with aging. [ABSTRACT FROM AUTHOR]

BACKGROUND: Although the pathogenic mechanisms of selective loss of motor neurons in amyotrophic lateral sclerosis (ALS) are unknown, there is increasing evidence for the hypothesis of an oxidative stress-related mitochondrial involvement as key determinant of motor neuron degeneration OBJECTIVE: The aim of our study has been to assess blood levels of peroxidation markers and to relate them to in-vivo oxidative metabolism in exercising muscle in patients affected by ALS. METHOD: For this purpose 10 patients (seven men and three women, mean age 58.5 ± 8.2 SD), performed an incremental bicycling test for the assessment of lipoperoxides and lactate during exercise. RESULTS: At rest, the ALS patients had higher than normal levels of both lactate (2.82 ± 0.76 mmol/L; normal range: 0.67-2.47 mmol/L) and lipoperoxides (361.7 ± 40.2 AU; normal range: 250-320 AU), the latter corresponding to a level of moderate oxidative stress. A further increment during exercise was observed both at lactate threshold and maximal power output levels. Values of blood lipoperoxides were significantly higher (P < 0.05) than those in control patients affected by chronic motor denervating processes of different origins and related (P < 0.01) to lactate production on exercising. CONCLUSIONS: These findings indicate the occurrence of an abnormally increased size of blood free radical pool in resting conditions and during exercise in ALS patients. The relationship between the levels of reactive oxygen species and lactate production is indicative of a tight link between mitochondrial function and oxidative stress in ALS. [ABSTRACT FROM AUTHOR]

Mitochondrial impairment has been implicated in the pathogenesis of the amyotrophic lateral sclerosis (ALS). Furthermore, mitochondrial-specific polymorphisms were previously related to other neurodegenerative diseases, such as Parkinson, Friedreich and Alzheimer disease. To investigate if specific genetic polymorphisms within the mitochondrial genome (mtDNA) could act as susceptibility factors and contribute to the clinical expression of sporadic ALS (sALS), we have genotyped predefined European mtDNA haplogroups in 222 Italian patients with sALS and 151 matched controls. Individuals classified as haplogroup I demonstrated a significant decrease in risk of ALS versus individuals carrying the most common haplogroup, H (odds ratio 0.08, 95% confidence interval 0.04–0.4, p < 0.01). Further stratification of the dataset by sex, age and site of onset of disease and survival failed to reach significance for association.Our study provides evidence of the contribution of mitochondrial variation to the risk of ALS development in Caucasians. Further it may help elucidate the mechanism of the mitochondrial dysfunction detectable in ALS, and may be of relevance in development of strategies for the treatment of this disease. [Copyright &y& Elsevier]

Increasing evidence indicates that mitochondrial dysfunction occurs in the central nervous system as well as in the peripheral tissues from Alzheimer’s disease (AD) patients. We have recently shown that mitochondrial cytochrome c oxidase (COX) activity is significantly reduced in brain and platelets from AD patients compared to controls. In the present study we investigated whether impaired COX activity could have functional consequences on energy metabolism. Blood lactate concentration was monitored at rest and during incremental exercise in 22 AD patients in whom COX activity in platelets was decreased compared to controls (35.7 ± 11.4 vs 48.4 ± 1.4 nmol/min/mg, P < 0.01). In both resting and exercising conditions, blood lactate was significantly higher in AD patients than in controls. Although the magnitude of exercise-related lactate accumulation was not different between the two groups, an anticipated anaerobic lactate threshold during the incremental forearm exercise was found in AD patients (50% of maximal voluntary contraction MVC compared to 60% in controls). COX activity was inversely related to lactate at a significant level for resting condition (r = −0.65) and borderline for anaerobic threshold exercise level. These results support the hypothesis of a systemic impairment of the mitochondrial function in AD and indicate that decreased COX activity could have functional consequences on metabolism. [Copyright &y& Elsevier]