Significance: Mitochondria play a critical role in the physiology of the heart by controlling cardiac metabolism, function, and remodeling. Accumulation of fragmented and damaged mitochondria is a hallmark of cardiac diseases. Recent Advances: Disruption of quality control systems that maintain mitochondrial number, size, and shape through fission/fusion balance and mitophagy results in dysfunctional mitochondria, defective mitochondrial segregation, impaired cardiac bioenergetics, and excessive oxidative stress. Critical Issues: Pharmacological tools that improve the cardiac pool of healthy mitochondria through inhibition of excessive mitochondrial fission, boosting mitochondrial fusion, or increasing the clearance of damaged mitochondria have emerged as promising approaches to improve the prognosis of heart diseases. Future Directions: There is a reasonable amount of preclinical evidence supporting the effectiveness of molecules targeting mitochondrial fission and fusion to treat cardiac diseases. The current and future challenges are turning these lead molecules into treatments. Clinical studies focusing on acute ( i.e ., myocardial infarction) and chronic ( i.e ., heart failure) cardiac diseases are needed to validate the effectiveness of such strategies in improving mitochondrial morphology, metabolism, and cardiac function. Antioxid. Redox Signal. 36, 844–863.

In understanding the pathology of neurological diseases, the role played by brain energy metabolism is gaining prominence. Animal models have demonstrated that regular physical exercise improves brain energy metabolism while also providing antidepressant, anxiolytic, antioxidant and neuroprotective functions. This review summarizes the latest evidence on the roles played by peroxisome proliferator-activated receptor gamma (PPAR-γ) coactivator 1-alpha (PGC-1α) and mitochondrial uncoupling protein (UCP) in this scenario. The beneficial effects of exercise seem to depend on crosstalk between muscles and nervous tissue through the increased release of muscle irisin during exercise.