Imbalanced OPA1 processing and mitochondrial fragmentation cause heart failure in mice

Abstract

Mitochondrial morphology is shaped by fusion and division of their membranes. Here, we found that adult myocardial function depends on balanced mitochondrial fusion and fission, maintained by processing of the dynamin-like guanosine triphosphatase OPA1 by the mitochondrial peptidases YME1L and OMA1. Cardiac-specific ablation of Yme1l in mice activated OMA1 and accelerated OPA1 proteolysis, which triggered mitochondrial fragmentation and altered cardiac metabolism. This caused dilated cardiomyopathy and heart failure. Cardiac function and mitochondrial morphology were rescued by Oma1 deletion, which prevented OPA1 cleavage. Feeding mice a high-fat diet or ablating Yme1l in skeletal muscle restored cardiac metabolism and preserved heart function without suppressing mitochondrial fragmentation. Thus, unprocessed OPA1 is sufficient to maintain heart function, OMA1 is a critical regulator of cardiomyocyte survival, and mitochondrial morphology and cardiac metabolism are intimately linked.

Mitophagy and mitochondrial biogenesis in atrial tissue of patients undergoing heart surgery with cardiopulmonary bypass

“…NDP52 and optineurin are recently identified autophagy adapter proteins that facilitate mitophagy in the CNS; however, their roles in the heart have not been described (7). Opa1 resides in the inner membrane of mitochondria and is important for maintaining mitochondrial fusion; its processing into a short form leads to mitochondrial fragmentation (8), which is a prerequisite for mitophagy (9). Induction of mitophagy was inferred from Parkin translocation to the mitochondrial heavy membrane fraction, depletion of both mitophagy adapters NDP52 and optineurin, and Opa1 processing to its short form in response to the surgery ( Figure 1, A-D).…”

The role of mitochondria in cardiac development and protection

“…Mitochondrial fission, budding off parts of the mitochondrial network, is essential for the identification of dysfunctional and senescent parts of the mitochondrial network and their removal by autophagy [46,73]. In addition, mitochondrial fusion is required for mitochondrial maintenance; it is not only essential for cardiomyocyte differentiation [74], but also for the healthy function of an adult heart [4,75]. However, it is not entirely clear why fragmentation of the mitochondrial network due to impaired fusion has deleterious consequences for the heart, especially as both respiratory chain activity and ATP production are not affected by it [75].…”

“…In addition, mitochondrial fusion is required for mitochondrial maintenance; it is not only essential for cardiomyocyte differentiation [74], but also for the healthy function of an adult heart [4,75]. However, it is not entirely clear why fragmentation of the mitochondrial network due to impaired fusion has deleterious consequences for the heart, especially as both respiratory chain activity and ATP production are not affected by it [75]. One explanation could be the maintenance of interaction between SSM and IFM at different depths of the cardiomyocyte.…”

“…Both age-related decline in cardiac contractility as well as developing cardiomyopathy result in specific loss of IFM function [71,138], which might be possible to counteract by promoting mitochondrial biogenesis, resulting not only in increased OXPHOS but also activating mitochondrial fission [4,62]. Interestingly, in mitochondrial fusion-deficient mice already a change to high-fat diet was enough to alter cardiac metabolism and prevent the development of cardiomyopathy [75].…”

Μitochondrial Membrane Dynamics and Inherited Optic Neuropathies

“…YME1L1 degrades both IMS and IM proteins, such as lipid transfer proteins (109), components of protein translocases of the IM (110,111), and OPA1 at S2 site (30,111,112). Depletion of YME1L1 was shown to cause increased mitochondrial fission and mitochondrial network fragmentation through acceleration of OMA1-dependent L-OPA1 cleavage, which leads to S-OPA1 accumulation (30,113), or through a mechanism involving DRP1 and MFF (114). Finally, loss of YME1L1 perturbs crista morphogenesis, and renders cells susceptible to apoptosis (115).…”