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The intriguing concept of exercise training as therapy for mitochondrial disease is currently unsettled: in the unique setting of mitochondrial heteroplasmy, what are the effects of chronic exercise on skeletal muscle containing a mixture of mutated and wild-type mitochondrial DNA (mtDNA)? Furthermore, what are the consequences of habitual physical inactivity on mitochondrial heteroplasmy? In patients with mtDNA defects, deleterious effects of limited physical activity likely magnify the mitochondrial oxidative impairment contributing to varying degrees of exercise intolerance. Normal adaptive responses to endurance training offer the potential to increase levels of functional mitochondria, improving exercise tolerance. The few clinical studies assessing such training effects in patients with mtDNA defects have unequivocally demonstrated physiologic and biochemical adaptations that improve exercise tolerance and quality of life. Uncertain, however, is the training effect on mitochondrial heteroplasmy. To determine therapeutic advisability of endurance training, it remains imperative to establish whether: reported increases in mutant mtDNA levels can be offset by increases in absolute wild-type mtDNA levels; and chronic physical inactivity leads to a selective down-regulation of wild-type mtDNA. Resistance exercise training offers an alternate, innovative therapeutic approach in patients with sporadic mtDNA mutations; exercise-induced transfer of normal mtDNA templates from muscle satellite cells to mature myofibers, thereby lowering mutation load (increasing functional mitochondrial load). Efficacy and safety of this approach needs to be replicated in a larger group of patients. Currently, appropriate recommendation (either in support or against) exercise training in mitochondrial disease is lacking, which is frustrating for physicians and disheartening for patients. Although considerable progress has been made, an immediate urgency exists to resolve the effects of chronic exercise on skeletal muscle in patients with heteroplasmic mtDNA mutations.