Controlling metabolism and cell death: at the heart of mitochondrial calcium signalling

Abstract

Transient increases in intracellular calcium concentration activate and coordinate a wide variety of cellular processes in virtually every cell type. This review describes the main homeostatic mechanisms that control Ca(2+) transients, focusing on the mitochondrial checkpoint. We subsequently extend this paradigm to the cardiomyocyte and to the interplay between cytosol, endoplasmic reticulum and mitochondria that occurs beat-to-beat in excitation-contraction coupling. The mechanisms whereby mitochondria decode fast cytosolic calcium spikes are discussed in the light of the results obtained with recombinant photoproteins targeted to the mitochondrial matrix of contracting cardiomyocytes. Mitochondrial calcium homeostasis is then highlighted as a crucial point of convergence of the environmental signals that mediate cardiac cell death, both by necrosis and by apoptosis. Altogether we point to a role of the mitochondrion as an integrator of calcium signalling and a fundamental decision maker in cardiomyocyte metabolism and survival.

Figure 1. Mechanisms of Ca²⁺ release from intracellular stores in cardiac and skeletal muscle

Schematic representation of the main Ca²⁺ release channel of the sarcoplasmic reticulum, the Ryanodine Receptor (RYR) and of the different mechanisms of activation of skeletal RYR1 and cardiac RYR2 by the L-type VOC/dihydropyridine receptor (DHPR). The main players in Ca²⁺ homeostasis are also represented. PMCA, plasma membrane Ca²⁺ ATPase, NCX, Na⁺/Ca²⁺ exchanger, SERCA, Sarco-endoplasmic reticulum ATPase. Red indicates high [Ca²⁺].

Figure 2. Microdomains of high [Ca²⁺]_c close to the mouth of the Ca²⁺ release channels are sensed by mitochondria

Schematic representation of ER-mitochondria contact sites and of their functional consequences. Ca²⁺ transients following InsP3 receptor (InsP3R) activation yield [Ca²⁺]_m increases which are higher than those measured in the bulk cytosol. A similar scenario can be envisaged for RYRs.

Figure 3. Functional hypotheses for the transduction of periodic cytosolic Ca²⁺ transients into changes of [Ca²⁺]_m

Data obtained in beating neonatal cardiomyocytes in culture show large beat-to-beat increases in [Ca²⁺]_m, thus favoring hypothesis II.