Protective Effect of Optic Atrophy 1 on Cardiomyocyte Oxidative Stress: Roles of Mitophagy, Mitochondrial Fission, and MAPK/ERK Signaling

Abstract

Myocardial infarction is associated with oxidative stress and mitochondrial damage. However, the regulatory mechanisms underlying cardiomyocyte oxidative stress during myocardial infarction are not fully understood. In the present study, we explored the cardioprotective action of optic atrophy 1- (Opa1-) mediated mitochondrial autophagy (mitophagy) in oxidative stress-challenged cardiomyocytes, with a focus on mitochondrial homeostasis and the MAPK/ERK pathway. Our results demonstrated that overexpression of Opa1 in cultured rat H9C2 cardiomyocytes, a procedure that stimulates mitophagy, attenuates oxidative stress and increases cellular antioxidant capacity. Activation of Opa1-mediated mitophagy suppressed cardiomyocyte apoptosis by downregulating Bax, caspase-9, and caspase-12 and upregulating Bcl-2 and c-IAP. Using mitochondrial tracker staining and a reactive oxygen species indicator, our assays showed that Opa1-mediated mitophagy attenuated mitochondrial fission and reduced ROS production in cardiomyocytes. In addition, we found that inhibition of the MAPK/ERK pathway abolished the antioxidant action of Opa1-mediated mitophagy in these cells. Taken together, our data demonstrate that Opa1-mediated mitophagy protects cardiomyocytes against oxidative stress damage through inhibition of mitochondrial fission and activation of MAPK/ERK signaling. These findings reveal a critical role for Opa1 in the modulation of cardiomyocyte redox balance and suggest a potential target for the treatment of myocardial infarction.

The role of circadian clock-controlled mitochondrial dynamics in diabetic cardiomyopathy

“…Downregulation of MNF2 expression prevents depolarization-induced translocation of Parkin to the damaged mitochondria and inhibits mitophagy (130), which contributes to the development of DCM (120). Likewise, DRP1 disruption in cardiomyocytes leads to imbalanced mitochondrial dynamics, and suppresses mitophagy via reducing the formation of autophagosomes, resulting in cardiac dysfunction (131). In cultured H9C2 cardiomyocytes, the overexpression of OPA1 promotes mitochondrial fusion and stimulates mitophagy, thereby attenuating high glucose-induced cardiomyocytes injury (132).…”

Current Understanding of the Pivotal Role of Mitochondrial Dynamics in Cardiovascular Diseases and Senescence

“…Opa1 heterozygous KO mice induce fragmentation of mitochondria, disorganization of cristae structures, and impair mitochondrial respiratory function ( 17 ). In contrast, overexpression of Opa1 promotes fragmented mitochondria, induces mitophagy, and increases antioxidant capacity, resulting in cardiomyocyte protection against oxidative stress through extracellular signal-regulated kinase (ERK) signaling ( 19 ). Taken together, normal mitochondrial fusion is essential to maintain normal cardiomyocyte function.…”