Journal Article

The physiological role of mitochondrial calcium revealed by mice lacking the mitochondrial calcium uniporter

Balaban, Robert S., Finkel, Toren, Pan, Xin, Liu, Chengyu, Springer, Danielle A., Liu, Jie, Aponte, Angel M., Gucek, Marjan, Fergusson, Maria M., Allen, Michele, Murphy, Elizabeth, Rovira, Ilsa I., Nguyen, Tiffany, Sun, Junhui, Teng, Yanjie

2013

Overview

Mitochondrial calcium has been postulated to regulate a wide range of processes from bioenergetics to cell death. Here, we characterize a mouse model that lacks expression of the recently discovered mitochondrial calcium uniporter (MCU). Mitochondria derived from MCU −/− mice have no apparent capacity to rapidly uptake calcium. Whereas basal metabolism seems unaffected, the skeletal muscle of MCU −/− mice exhibited alterations in the phosphorylation and activity of pyruvate dehydrogenase. In addition, MCU −/− mice exhibited marked impairment in their ability to perform strenuous work. We further show that mitochondria from MCU −/− mice lacked evidence for calcium-induced permeability transition pore (PTP) opening. The lack of PTP opening does not seem to protect MCU −/− cells and tissues from cell death, although MCU −/− hearts fail to respond to the PTP inhibitor cyclosporin A. Taken together, these results clarify how acute alterations in mitochondrial matrix calcium can regulate mammalian physiology. Until the recent discovery of the mitochondrial calcium uniporter (MCU), the effect of increases in mitochondrial calcium levels could not be tested in vivo . Finkel and colleagues have knocked out the gene coding for MCU in adult mice, and show that MCU is required for transport of calcium into the mitochondria. They also show that, in its absence, the function of skeletal muscle is altered; however, surprisingly, no effects are observed on the sensitivity to cell-death-inducing agents.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/80/642/333 / 631/80/82 / 631/80/86/2372 / Animals / Apoptosis / Bioenergetics / Biological transport / Calcium / Calcium - physiology / Calcium Channels - deficiency / Calcium Channels - genetics / Calcium, Dietary / Cancer Research / Cardiotonic Agents - pharmacology / Cell Biology / Cell death / Cells, Cultured / Dehydrogenase / Developmental Biology / Exercise Tolerance - genetics / Female / Fibroblasts - metabolism / Genetic Association Studies / Heart / Isoproterenol - pharmacology / Life Sciences / Male / Mammals / Metabolism / Mice / Mice, Knockout / Mitochondria / Mitochondria, Muscle - metabolism / Mitochondrial Membrane Transport Proteins - metabolism / Mitochondrial Permeability Transition Pore / Mortality / Muscle, Skeletal - metabolism / Muscle, Skeletal - physiology / Musculoskeletal system / Myocardial Reperfusion Injury - metabolism / Myocytes, Cardiac - drug effects / Myocytes, Cardiac - metabolism / Permeability / Phenotype / Physiological aspects / Physiology / Pyruvate Dehydrogenase Complex - metabolism / Signal transduction / Stem Cells