Rescue and Role of Complex I in myocardial ischemic injury

San Diego State University, San Diego CA

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): Considerable progress has been made in our understanding of apoptosis mediated by permeabilization of the mitochondrial membrane by pro-apoptotic Bcl-2 family members. However, in the context of myocardial ischemia/reperfusion injury, a significant mechanism of cell death is catastrophic mitochondrial swelling mediated by the mitochondrial permeability transition pore (MPTP). In our studies of HL-1 myocytes subjected to simulated ischemia and reperfusion, Bax and Bid recruitment to mitochondria occurs after and is dependent upon MPTP. We propose to determine whether this is the case in vivo. In ischemia/reperfusion, a mitochondrial phospholipase (iPLA2) is activated and liberates arachidonic acid, which contributes to superoxide production and cell death through activation of the MPTP. We propose to identify the relevant target of arachidonic acid in the mitochondrion. The established view of the MPTP comprising VDAC in the outer membrane, ANT in the inner membrane, and cyclophilin D (matrix/inner membrane) has been questioned in light of recent studies showing that the MPTP can still open in VDAC-null mice, ANT-null mice, and cyclophilin D-null mice, although the threshold is altered. Evidence that has accumulated in parallel to the traditional view of the MPTP has implicated oxidative phosphorylation Complex I as a key element in the MPTP. We now present new evidence derived from cyclophilin D-overexpressing mice that further supports a role for Complex I in the MPTP. We hypothesize that arachidonic acid and cyclophilin D interact with Complex I to regulate pore opening. PUBLIC HEALTH RELEVANCE: Understanding the molecular processes that take place during and after a heart attack may lead to new therapies for ischemic heart disease and heart failure. We will explore the basis for catastrophic mitochondrial swelling in myocardial ischemia and reperfusion. We will identify the fatty acids that contribute to mitochondrial damage, as well as the mitochondrial proteins that are involved. We will develop a novel protein therapy for treatment of heart damage after a heart attack that will bypass the damaged mitochondrial enzyme complex to restore function.