MitoFORMSinHF · Mitochondrial cristae form, function, and organization dependent upon metabolic sources and implication in heart failure

Mitochondrial cristae form, function, and organization dependent upon metabolic sources and implication in heart failure

Acute myocardial infarctions (AMIs) are the leading cause of mortality worldwide and lead to the vast majority of heart failure (HF) cases. While recently there has been a decline in AMIs leading to mortality due to advancements in managing the disease, the prevalence of HF is only increasing. Mitochondria are double membrane organelles that synthesize most cellular ATP, but they also mediate death signals by initiating intrinsic apoptosis and necrosis, implicating their role in nearly all pathophysiology including acute myocardial infarction (AMI) and heart failure (HF). Mitochondria are dynamic and the size, shape, and number of mitochondria respond to changes in the cellular environment. Mitochondrial dynamics are regulated by a dynamin related family of proteins that control fusion and fission of mitochondria. At the level of the inner mitochondrial membrane, Optic Atrophy 1 (OPA1), a dynamin-related protein, orchestrates IMM fusion but also has a genetically distinct role in maintaining mitochondrial cristae form and ultrastructure. Opa1-mediated cristae maintenance is implicated in cardiac ischemia-reperfusion injury (I/R) as apoptotic signaling disassemble Opa1 oligomers, allowing cytochrome c to release to the cytosol, inducing intrinsic apoptosis and cell death. Recent studies indicate metabolism can profoundly influence mitochondrial morphology as starvation increases mitochondrial fusion events and enhances cristae density in an Opa1-dependent manner but it is unclear how specific carbon sources regulate Opa1-mediated cristae maintenance and how this is implicated in acute ischemia reperfusion injury or heart failure. In the MitoFORMsinHF project we hypothesized OPA1 assembly and cristae maintenance are dependent on metabolic substrate utilization and are implicated in I/R damage pathogenesis. The overall objective of the MitoFORMSinHF project assessed if shifting metabolism can prevent pathogenic cristae remodeling and provide cardioprotective benefits during I/R injury. This is important for society as these novel descriptions of unknown mechanisms-of-action of crosstalk between single carbon sources and IMM architecture will be exploited by the scientific community and biotech sector to translate the basic science into potential novel therapeutic targets for I/R injury or HF.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз