AKIP1 protects against cardiac injury via enhanced mitochondrial function

Abstract

Cardiovascular disease is a leading cause of morbidity and mortality in the United States but the signaling mechanisms leading to protection are poorly understood. Protein kinase A (PKA) has been implicated in regulating cardiac contractility, gene expression and metabolism. However, PKA has dichotomous roles and is implicated in both, cell survival and cell death. We identified protein kinase A interacting protein (AKIP1) as a modulator that responds to oxidative stress; when up regulated, it shows adaptation to ischemic injury. We hypothesized that AKIP1 plays a critical role in regulating mitochondria to affect protection. AKIP1 gene transferred hearts showed increased mitochondrial localization of AKIP1 and the mitochondria had 1) decreased reactive oxygen species generation, 2) enhanced calcium tolerance, 3) decreased cytochrome C release, and 4) enhanced PKA signaling. Further we show interaction of AKIP1 with the mitochondrial apoptosis inducing factor (AIF); where upon hypoxic and oxidant stress these proteins show increased expression and interaction. Therefore, we infer that AKIP1 is a key molecular scaffold that assembles PKA/AIF complexes at the mitochondria to alter the physiological response of the heart to stress. Understanding the molecular activity and regulation of AKIP1 may provide a novel therapeutic approach for limiting myocardial injury.