Mitochondrial Ca²⁺ in heart failure: Not enough or too much?

Ca²⁺ serves as a ubiquitous second messenger mediating a variety of cellular processes including electrical excitation, contraction, gene expression, secretion, cell death and others. The identification of the molecular components of the mitochondrial Ca²⁺ influx and efflux pathways has created a resurgent interest in the regulation of mitochondrial Ca²⁺ balance and its physiological and pathophysiological roles. While the pace of discovery has quickened with the availability of new cellular and animal models, many fundamental questions remain to be answered regarding the regulation and functional impact of mitochondrial Ca²⁺ in health and disease. This review highlights several experimental observations pertaining to key aspects of mitochondrial Ca²⁺ homeostasis that remain enigmatic, particularly whether mitochondrial Ca²⁺ signaling is depressed or excessive in heart failure, which will determine the optimal approach to therapeutic intervention.