Proteolytic control of mitochondrial dynamics and metabolism

Abstract

Mitochondria are deeply integrated into cellular metabolism. The many metabolic functions of mitochondria have been intimately linked to their morphology, which is shaped by ongoing events of fusion and fission of outer and inner membranes. Unopposed fission causes mitochondrial fragmentation, which is generally associated with metabolic dysfunction and disease. Unopposed fusion results in a hyperfused network and serves to counteract metabolic insults, preserve cellular integrity and protect against autophagy.

The dynamic behavior of mitochondria is controlled by proteolytic processing of the dynamin-like GTPase OPA1, which mediates fusion and preserves mitochondrial structure. Uncleaved OPA1 is sufficient for fusion, which is limited by OPA1 cleavage by the inner membrane peptidases YME1L and OMA1 at two distinct sites. Whereas various cellular stress conditions activate OMA1, YME1L is regulated by metabolic cues. Stress-induced processing of OPA1 by OMA1 and mitochondrial fragmentation in cardiomyocytes is associated with altered fuel utilization and culminates in heart failure, which can be suppressed by metabolic interventions, such as feeding with high fat diet. Thus, mitochondrial morphology and metabolism are intimately coupled: metabolic needs determine mitochondrial structure and, conversely, alterations in mitochondrial dynamics impact on cellular metabolism.