Why don't mice lacking the mitochondrial Ca2+ uniporter experience an energy crisis?

Current dogma holds that the heart balances energy demand and supply effectively and sustainably by sequestering enough Ca2+ into mitochondria during heartbeats to stimulate metabolic enzymes in the tricarboxylic acid (TCA) cycle and electron transport chain (ETC). This process is called excitation-contraction-bioenergetics (ECB) coupling. Recent breakthroughs in identifying the mitochondrial Ca2+ uniporter (MCU) and its associated proteins have opened up new windows for interrogating the molecular mechanisms of mitochondrial Ca2+ homeostasis regulation and its role in ECB coupling. Despite remarkable progress made in the past 7 years, it has been surprising, almost disappointing, that germline MCU deficiency in mice with certain genetic background yields viable pups, and knockout of the MCU in adult heart does not cause lethality. Moreover, MCU deficiency results in few adverse phenotypes, normal performance, and preserved bioenergetics in the heart at baseline. In this review, we briefly assess the existing literature on mitochondrial Ca2+ homeostasis regulation and then we consider possible explanations for why MCU-deficient mice are spared from energy crises under physiological conditions. We propose that MCU and/or mitochondrial Ca2+ may have limited ability to set ECB coupling, that other mitochondrial Ca2+ handling mechanisms may play a role, and that extra-mitochondrial Ca2+ may regulate ECB coupling. Since the heart needs to regenerate a significant amount of ATP to assure the perpetuation of heartbeats, multiple mechanisms are likely to work in concert to match energy supply with demand.