Bioenergetics and cell death

Abstract

Mitochondrial bioenergetic function is a key to cell life and death. Cells need energy not only to support their vital functions but also to die gracefully. Execution of an apoptotic program includes energy-dependent steps, including kinase signaling, formation of the apoptosome, and effector caspase activation. Under conditions of bioenergetic collapse, cells are diverted toward necrotic demise. Mitochondrial outer membrane permeabilization (MOMP) is a decisive event in the execution of apoptosis. It is also causally linked to a decline in bioenergetic function via different mechanisms, not merely due to cytochrome c dispersion. MOMP-induced bioenergetic deficiency is usually irreversible and commits cells to die, even when caspases are inactive. Here, we discuss the mechanisms by which MOMP impacts bioenergetics in different cell death paradigms.

Figure 1

Mitochondrial respiration driven by oxidation of external NADH in digitonin-permeabilized HeLa cells. The cells (13 × 10⁶ per mL) were permeabilized with 0.012% digitonin in a KCl-based incubation medium containing 10 mM succinate and 0.5 µM rotenone. Arrows indicate additions of the cells, 100 nM FCCP (an uncoupler), 2 µM myxothiazol (a Complex III inhibitor), 2 mM NADH, and cytochrome c (CytC, final concentration—80 µM). Complex IV inhibitor KCN (0.5 mM) was added at the end of the runs to terminate respiration. Curve (a) cells were treated with 0.5 µM staurosporine (in the presence of 100 µM ZVAD) for 12 h; curve (b) control cells; curves (c) and (d) digitonin-permeabilized cells were pretreated with 40 nM tBid for 5 min prior to the respiration measurements in the presence (c) or absence (d) of NADH. Numbers under the curves are respiration rates (µM O₂ per min). Note that cytochrome c markedly stimulated respiration in staurosporine and tBid-treated cells (a, c) in the presence of exogenous NADH.