Mitochondrial mutations as determinants of beneficial versus maleficial exercise response in mouse models for mitochondrial diseases (Mitosport)

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Primary mitochondrial disorders are now recognized as the most common class of metabolic disorders affecting an estimate 1 in 4200 individuals. Furthermore, mitochondrial dysfunction has been implicated in a wide range of common diseases from diabetes to Alzheimer’s disease. Yet, there are no proven therapeutic interventions for mitochondrial disease. Exercise has been found to be beneficial for diabetes and Alzheimer’s disease indicating that appropriate exercise regimes might be beneficial for primary mitochondrial disease as well. However, primary mitochondrial diseases are genetically diverse involving hundreds of mutations in both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) genes. Accordingly, I hypothesize that specific exercise regimes will be beneficial for some mitochondrial disorders but contraindicated in others dependent on the underlying mitochondrial defect.The Center for Mitochondrial and Epigenomic Medicine (CMEM) has developed a unique series of viable mouse models of mitochondrial disease, among which are mutations in the mtDNA complex I (ND6P25L) and IV (COIV421A) genes and in the adenine nucleotide translocator 1 (Ant1). These mutant mice encompass a wide range of mitochondrial dysfunction and thus provide an exceptional and powerful opportunity to expose different mitochondrial defects to controlled exercise regimes followed by detailed physiological and biochemical analyses. On the molecular level, exercise adaptions are mediated via metabolite and redox changes like the NAD/NADH ratio, which can be determined microscopically with high spatial resolution.By combining CMEM’s mouse models with my expertise in redox imaging I am now in a unique position to clarify the interrelation between mitochondrial mutations, exercise response, and the underlying molecular pathways. This will open the possibility of personalized clinical advice for mitochondrial patients regarding beneficial physical activity, as well as obtain deep insight into the therapeutic basis of exercise for common diseases.I will pursue 3 specific aims:Specific Aim 1: Determination of the exercise physiology of the mitochondrial mutant mice and their acute response to an exercise stimulus. The daily activity and the response to an acute exercise stress test (VO2max) will be assessed and correlated with changes in redox state, metabolite levels, signaling pathway changes and inflammatory response.Specific Aim 2: Assess the exercise adaptions of the mitochondrial mutant mice upon an exercise protocol. The mice will be exposed to a 6 week exercise protocol to assess their mitochondrial responses in physiology, respiratory complex activity, metabolites, and signaling pathways.Specific Aim 3: Elucidate the physiological basis of the exercise response by evaluating nicotinamide riboside and AICAR as exercise mimetics. I will evaluate the effects on exercise capacity of the mutant mice by altering their NAD/NADH ratio or ADP/ATP ratio specifically.