Effects of Dynamin‐Related Protein‐1 (DRP‐1) Inhibition with MDIVI‐1 on Myocardial Injury, Mitochondrial Respiration and Stress‐Signalling in the Murine Heart

Abstract

Mitochondrial fission protein, dynamin‐related protein‐1 (DRP‐1), may be a key determinant of cardiac resistance to ischemia‐reperfusion (I‐R) and other stresses. We examined the impact of I‐R on myocardial expression of DRP‐1 (together with Akt and Erk1/2), mitochondrial respiration, and injury in I‐R hearts in 4mo male C57Bl/6 mice subject to DRP‐1 inhibition. Functional recoveries of Langendorff perfused hearts subjected to 25 min ischemia/45 min reperfusion were significantly improved by pre‐treatment with 1 µM MDIVI‐1. Cell death (LDH efflux) was only modified by a higher 5 µM concentration. Protective effects were not replicated by an alternate inhibitor dynasore hydrate (1 µM). Ischemic insult repressed mitochondrial O 2 consumption during early reperfusion, with a ~50% fall in complex I activity that was effectively reversed by MDIVI‐1. Functional benefits were associated with MDIVI‐1 dependent reductions in mitochondrial DRP‐1 expression and cytosolic Erk1/2 phosphorylation during I‐R, while phosphorylation of cardiac Akt was significantly augmented by MDIVI‐1. A similar pattern was evident in parallel studies of H 2 O 2 (400 µM) challenged H9c2 myoblasts, with MDIVI‐1 negating oxidative‐stress Erk1/2 phosphorylation whereas phosphoactivation of Akt was preserved. These data support a key role for DRP‐1 in repressing I‐R tolerance, mitochondrial function, and protective Akt phosphorylation (whilst also augmenting Erk1/2 activation). This role of DRP‐1 in control of stress‐resistance, mitochondrial function and survival‐kinase signalling supports the potential value of targeting the protein to protect ischemic myocardium.