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The cytochrome-b5 reductase (CYB5R) family of flavoproteins is known to regulate reduction-oxidation (redox) balance in cells. The five enzyme members are highly compartmentalized at the subcellular level and function as "redox switches" enabling the reduction of several substrates, such as heme and coenzyme Q. Critical insight into the physiological and path-ophysiological significance of CYB5R enzymes has been gleaned from several human genetic variants that cause congenital disease and a broad spectrum of chronic human diseases. Among the CYB5R genetic variants, CYB5R3 is well-characterized and deficiency in expression and activity is associated with type II methemoglobinemia, cancer, neurode-generative disorders, diabetes, and cardiovascular disease. Importantly, pharmacological and genetic-based strategies are underway to target CYB5R3 to circumvent disease onset and mitigate severity. Despite our knowledge of CYB5R3 in human health and disease, the other reductases in the CYB5R family have been understudied, providing an opportunity to unravel critical function(s) for these enzymes in physiology and disease. In this review, we aim to provide the broad scientific community an up-to-date overview of the molecular, cellular, physiological, and pathophysiological roles of CYB5R proteins. [ABSTRACT FROM AUTHOR]

Coenzyme Q (CoQ) is ubiquitously embedded in lipid bilayers of various cellular organelles. As a redox cycler, CoQ shuttles electrons between mitochondrial complexes and extramitochondrial reductases and oxidases. In this way, CoQ is crucial for maintaining the mitochondrial function, ATP synthesis, and redox homeostasis. Cardiomyocytes have a high metabolic rate and rely heavily on mitochondria to provide energy. CoQ levels, in both plasma and the heart, correlate with heart failure in patients, indicating that CoQ is critical for cardiac function. Moreover, CoQ supplementation in clinics showed promising results for treating heart failure. This review provides a comprehensive view of CoQ metabolism and its interaction with redox enzymes and reactive species. We summarize the clinical trials and applications of CoQ in heart failure and discuss the caveats and future directions to improve CoQ therapeutics. [Display omitted] • CoQ is an indispensable component in the mitochondrial respiratory chain. • The redox status of CoQ is regulated by mitochondrial complexes and other enzymes in different subcellular compartments. • CoQ, in both reduced and oxidized forms, interacts with a myriad of reactive species. • CoQ has been implemented in treating cardiovascular disease for decades and showed potentials as a therapy for heart failure. • More rigorous clinical trials are needed to appreciate CoQ's clinical value as a therapeutic approach against heart failure. [ABSTRACT FROM AUTHOR]

Objectives: Brain mitochondrial dysfunction limits neurologic recovery after cardiac arrest. Brain polyunsaturated cardiolipins, mitochondria-unique and functionally essential phospholipids, have unprecedented diversification. Since brain cardiolipins are not present in plasma normally, we hypothesized their appearance would correlate with brain injury severity early after cardiac arrest and return of spontaneous circulation.Design: Observational case-control study.Setting: Two medical centers within one city.Participants (subjects): We enrolled 41 adult cardiac arrest patients in whom blood could be obtained within 6 hours of resuscitation. Two subjects were excluded following outlier analysis. Ten healthy subjects were controls. Sprague-Dawley rats were used in asphyxial cardiac arrest studies.Interventions: None.Measurements and Main Results: We developed a high-resolution liquid chromatography/mass spectrometry method and determined cardiolipins speciation in human brain, heart, and plasma within 6 hours of (return of spontaneous circulation) from 39 patients with cardiac arrest, 5 with myocardial infarction, and 10 healthy controls. Cerebral score was derived from brain-specific cardiolipins identified in plasma of patients with varying neurologic injury and outcome. Using a rat model of cardiac arrest, cardiolipins were quantified in plasma, brain, and heart. Human brain exhibited a highly diverse cardiolipinome compared with heart that allowed the identification of brain-specific cardiolipins. Nine of 26 brain-specific cardiolipins were detected in plasma and correlated with brain injury. The cerebral score correlated with early neurologic injury and predicted discharge neurologic/functional outcome. Cardiolipin (70:5) emerged as a potential point-of-care marker predicting injury severity and outcome. In rat cardiac arrest, a significant reduction in hippocampal cardiolipins corresponded to their release from the brain into systemic circulation. Cerebral score was significantly increased in 10 minutes versus 5 minutes no-flow cardiac arrest and naïve controls.Conclusions: Brain-specific cardiolipins accumulate in plasma early after return of spontaneous circulation and proportional to neurologic injury representing a promising novel biomarker. [ABSTRACT FROM AUTHOR]

The nitric oxide/soluble guanylyl cyclase (NO-sGC) signaling pathway regulates the cardiovascular, neuronal, and gastrointestinal systems. Impaired sGC signaling can result in disease and system-wide organ failure. This review seeks to examine the redox control of sGC through heme and cysteine regulation while discussing therapeutic drugs that target various conditions. Heme regulation involves mechanisms of insertion of the heme moiety into the sGC protein, the molecules and proteins that control switching between the oxidized (Fe 3+ ) and reduced states (Fe 2+ ), and the activity of heme degradation. Modifications to cysteine residues by S-nitrosation on the α1 and β1 subunits of sGC have been shown to be important in sGC signaling. Moreover, redox balance and localization of sGC is thought to control downstream effects. In response to altered sGC activity due to changes in the redox state, many therapeutic drugs have been developed to target decreased NO-sGC signaling. The importance and relevance of sGC continues to grow as sGC dysregulation leads to numerous disease conditions. [ABSTRACT FROM AUTHOR]