Metabolic rescue ameliorates mitochondrial encephalo-cardiomyopathy in murine and human iPSC models of Leigh syndrome.

BACKGROUND: Mice with deletion of complex I subunit Ndufs4 develop mitochondrial encephalomyopathy resembling Leigh syndrome (LS). The metabolic derangement and underlying mechanisms of cardio-encephalomyopathy in LS remains incompletely understood. METHODS: We performed echocardiography, electrophysiology, confocal microscopy, metabolic and molecular/morphometric analysis of the mice lacking Ndufs4. HEK293 cells, human iPS cells-derived cardiomyocytes and neurons were used to determine the mechanistic role of mitochondrial complex I deficiency. RESULTS: LS mice develop severe cardiac bradyarrhythmia and diastolic dysfunction. Human-induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs) with Ndufs4 deletion recapitulate LS cardiomyopathy. Mechanistically, we demonstrate a direct link between complex I deficiency, decreased intracellular (nicotinamide adenine dinucleotide) NAD+ /NADH and bradyarrhythmia, mediated by hyperacetylation of the cardiac sodium channel NaV 1.5, particularly at K1479 site. Neuronal apoptosis in the cerebellar and midbrain regions in LS mice was associated with hyperacetylation of p53 and activation of microglia. Targeted metabolomics revealed increases in several amino acids and citric acid cycle intermediates, likely due to impairment of NAD+ -dependent dehydrogenases, and a substantial decrease in reduced Glutathione (GSH). Metabolic rescue by nicotinamide riboside (NR) supplementation increased intracellular NAD+ / NADH, restored metabolic derangement, reversed protein hyperacetylation through NAD+ -dependent Sirtuin deacetylase, and ameliorated cardiomyopathic phenotypes, concomitant with improvement of NaV 1.5 current and SERCA2a function measured by Ca2+ -transients. NR also attenuated neuronal apoptosis and microglial activation in the LS brain and human iPS-derived neurons with Ndufs4 deletion. CONCLUSIONS: Our study reveals direct mechanistic explanations of the observed cardiac bradyarrhythmia, diastolic dysfunction and neuronal apoptosis in mouse and human induced pluripotent stem cells (iPSC) models of LS.

Nutrition and Nutraceuticals in Neuroinflammatory and Brain Metabolic Stress: Implications for Neurodegenerative Disorders.

BACKGROUND AND OBJECTIVE: A steep rise in the incidences of neurodegenerative disorders could be the combined effect of several non-genetic factors such as increased life expectancy, environmental pollutants, lifestyle, and dietary habits, as population-level genetic change require multiple generations. Emerging evidence suggests that chronic over-nutrition induces brain metabolic stress and neuroinflammation, and are individually known to promote neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD). Although the association of metabolic disorders such as diabetes, hypertension, dyslipidemia, and atherosclerosis with the dietary habits is well known, neuronal implications of diet and nutritional factors is still in its infancy. Transcriptomics and proteomics-based studies support the view that nutraceuticals target multiple neuroprotective pathways in a slow but effective manner without causing severe adverse effects, and may represent the future of tackling neurodegenerative disorders. CONCLUSION: In this article we i) review the diet/dietary supplement connection with brain metabolic stress and neuroinflammation and ii) summarize current knowledge of the effects of nutraceuticals on neurodegenerative disorders.

Nutraceuticals against Neurodegeneration: A Mechanistic Insight.

The mechanisms underlying neurodegenerative disorders are complex and multifactorial; however, accumulating evidences suggest few common shared pathways. These common pathways include mitochondrial dysfunction, intracellular Ca2+ overload, oxidative stress and inflammation. Often multiple pathways co-exist, and therefore limit the benefits of therapeutic interventions. Nutraceuticals have recently gained importance owing to their multifaceted effects. These food-based approaches are believed to target multiple pathways in a slow but more physiological manner without causing severe adverse effects. Available information strongly supports the notion that apart from preventing the onset of neuronal damage, nutraceuticals can potentially attenuate the continued progression of neuronal destruction. In this article, we i) review the common pathways involved in the pathogenesis of the toxicants-induced neurotoxicity and neurodegenerative disorders with special emphasis on Alzheimer`s disease (AD), Parkinson`s disease (PD), Huntington`s disease (HD), Multiple sclerosis (MS) and Amyotrophic lateral sclerosis (ALS), and ii) summarize current research advancements on the effects of nutraceuticals against these detrimental pathways.

Use of chemoprotectants in chemotherapy and radiation therapy: the challenges of selecting an appropriate agent.

Chemoprotection refers to the protection from the toxicity of one chemical by the intervention of another. Conflicting preclinical and clinical reports make it difficult to either ignore or accept the use of chemoprotectants during cancer chemotherapy or radiotherapy. The selection of anticancer drugs depends on the type and stage of cancer development. However, very little attention has been paid to the selection of chemoprotectants. The answer to the use of chemoprotectants during cancer therapy lies in their appropriate selection in a case-specific and/or issue-specific manner. The need of the hour is to find better answers on the rationality of chemoprotectants selection during cancer therapy using cutting-edge science. In this commentary, we have presented few examples to justify our view-points.