Alcohol and Mitochondria in Cardiac Apoptosis: Mechanisms and Visualization

Abstract

Apoptosis of myocytes is likely to contribute to a variety of heart conditions and could also be important in the development of alcoholic heart disease. A fundamental pathway to apoptosis is through mitochondrial membrane permeabilization and release of proapoptotic factors from the mitochondrial intermembrane space to the cytosol. The authors' results show that prolonged exposure of cultured cardiac cells to ethanol (35 mM for 48 hr) promotes Ca2+-induced activation of the mitochondrial permeability transition pore (PTP). PTP-dependent mitochondrial membrane permeabilization is followed by release of cytochrome c and execution of apoptosis. The authors propose that chronic ethanol exposure, in combination with other stress signals, may allow for activation of the PTP by physiological calcium oscillations, providing a trigger for cardiac apoptosis during chronic alcohol abuse. Coincidence of apoptosis promoting factors occurs in only a small fraction of myocytes, but because of the absence of regeneration, even a modest increase in the rate of cell death may contribute to a decrease in cardiac contractility. Detection of apoptotic changes that are present in only a few myocytes at a certain time in the heart is not feasible with most of the apoptotic assays. Fluorescence imaging is a powerful technology to visualize changes that are confined to a minor fraction of cells in a tissue, and the use of multiphoton excitation permits imaging in situ deep in the wall of the intact heart. This article discusses potential mechanisms of the effect of alcohol on mitochondrial membrane permeabilization and visualization of mitochondria-dependent apoptosis in cardiac muscle.