Beneficial effects of physical activity on mitochondrial health are well substantiated in the scientific literature, with regular exercise improving mitochondrial quality and quantity in normal healthy population, and in cardiometabolic and neurodegenerative disorders and aging. However, several recent studies questioned this paradigm, suggesting that extremely heavy or exhaustive exercise fosters mitochondrial disturbances that could permanently damage its function in health and disease. Exercise-induced mitochondrial dysfunction (EIMD) might be a key proxy for negative outcomes of exhaustive exercise, being a pathophysiological substrate of heart abnormalities, chronic fatigue syndrome (CFS) or muscle degeneration. Here, we overview possible factors that mediate negative effects of exhaustive exercise on mitochondrial function and structure, and put forward alternative solutions for the management of EIMD.

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