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AIFm2 mediated retrograde stress signaling during ischemia‐reperfusion injury in heart: Role of 4‐HNE adduction

Myocardial ischemia‐reperfusion injury results from restoration of normal coronary blood circulation after a prolonged period of circulatory arrest. Oxidative stress is one of the underlying mechanism for the pathogenesis of ischemia‐reperfusion injury. Oxidative stress results from a disturbance in the homeostatic balance between free radicle generation and availability of antioxidant molecule to scavenge them. Manganese superoxide dismutase (MnSOD), mitochondrial based antioxidant is capable of converting superoxide radical (O2•−) into oxygen. Reactive oxygen species cause lipid peroxidation and subsequent production of 4‐hydroxy‐2‐nonenal (4‐HNE) from polyunsaturated fatty acid (PUFA). 4‐HNE can modify signaling by causing adduction of cellular components such as proteins and nucleic acids. Mice lacking MnSOD specifically in cardiomyocyte (Myh6‐SOD2Δ) showed early mortality (~ 4 months) due to mitochondrial dysfunction and subsequent cardiomyopathy. Myh6‐SOD2Δ mice also had decreased mitochondrial respiration and cardiac performance shown by Seahorse XF analyzer and M‐mode echocardiography respectively. Following ischemia‐reperfusion injury, MnSOD expression was reduced shown by Real‐Time PCR array, Immunoblot, and Immunohistochemistry. Immunoblot analysis of AIFm2 showed increased expression in the ischemic heart. Normally AIFm2 localized to mitochondria, however, following ischemia 4‐HNE adducted AIFm2 translocated from mitochondria to nucleus thereby binding to DNA and resultant myocardial apoptosis. With the help of mass spectrometric analysis, it has been shown that His 174 and Cys 187 are two sites of AIFm2 where 4‐HNE adduction occurs. These results identify the role of 4‐HNE adduction in the regulation of mitochondrial retrograde signaling mediator protein apoptosis‐inducing factor associated mitochondrion protein 2 (AIFm2) during myocardial ischemia‐reperfusion injury.