Circadian Control Of Mitochondrial Dynamics And Its Implication In Aging

The circadian clock promotes metabolic efficiency by pre-programmed regulation of metabolic pathways in anticipation of the upcoming feeding/fasting cycle. Recent studies have suggested that the master circadian regulators Bmal1/Clock play an important role in controlling mitochondrial function, including oxidative metabolism and mitochondrial dynamics. The latter includes mitochondrial fusion, fission, and selective autophagy (mitophagy) that follows fission. These processes not only allow mitochondria to undergo architectural/organizational changes in response to different nutrient conditions but also ensure quality control by removing damaged components through mitophagy. Results from mouse genetic models indicate that Bmal1-dependent regulation of fission and mitophagy genes reduces oxidative stress and maintains metabolic flexibility in the liver. In addition, aha-1, a C. elegans Bmal1 homologue, is required for orderly organizations of muscle mitochondria. Interestingly, Baml1 whole body knockout mice develop premature aging phenotypes, while AHA-1 over-expression increases lifespan in worms. Given that mitochondrial dysfunction appears to be a common feature associated with aging, obesity, and related metabolic diseases, these findings implicate an evolutionarily conserved regulatory mechanism that links mitochondrial fidelity to lifespan and/or healthspan.