Mitochondrial biogenesis, genetics and cell loss in mammalian aging

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PROJECT SUMMARY/ABSTRACT Mitochondrial biogenesis is a target of many aging interventions. While the induction of mitochondrial biogenesis is generally thought to be beneficial, our data indicate that activating mitochondrial biogenesis at old age drives the intracellular accumulation of mitochondrial DNA (mtDNA) deletion mutations and results in an 18% loss of muscle fibers and a 1,200% increase in electron transport chain (ETC) deficient muscle fiber segments. These effects were antagonistically pleiotropic; they were not observed in treated young rats. Based on our data, up-regulation of mitochondrial biogenesis in aged humans may cause significant skeletal muscle damage. These studies will clarify the role of mitochondrial biogenesis in mtDNA deletion mutation accumulation and evaluate the old-age specific effects of compounds that stimulate mitochondrial biogenesis in skeletal muscle. Project outcomes: · Specify the cellular pathways and ages at which inducing mitochondrial biogenesis increases mtDNA deletion mutation frequency, ETC deficiencies and fiber loss. · Infer the causality of mitochondrial biogenesis in fiber loss by specifying the order of events and time required between mitochondrial biogenesis, mtDNA deletion mutation accumulation and cell death. · Determine whether other AMPK or peroxisome proliferator-activated receptor agonists, which target mitochondrial biogenesis, also induce deletion mutation accumulation and cell death when initiated at old ages. · Downregulate mitochondrial biogenesis in old rats to prevent ETC deficiencies and fiber loss. By understanding the mechanisms and impacts of inducing mitochondrial biogenesis at old ages, we will specify targets and treatment strategies that mitigate the antagonistic effects.