The contribution of dynamic regulation of mitochondrial calcium uptake to liver pathophysiology

Calcium (Ca2+) signaling regulates numerous functions of the liver. The Ca2+signaling machinery and the spatiotemporal patterning of Ca2+ signals allows Ca2+ to control yet discriminate between all these diverse functions. Defects in this machinery and patterning can lead to pathological conditions. Mitochondria form an integral part of this machinery, both as regulators and targets of Ca2+ signaling. Also, the organization of Ca2+ signaling is not only coordinated intracellularly but extends among a complex intercellular communication network across the hepatic lobule. Chronic alcohol consumption leads to alterations in mitochondrial morphology and function but the mechanisms of alcohol-induced mitochondrial dysfunction is not fully understood. In this study we report mitochondrial ultrastructural changes in rat livers under chronic ethanol exposure. These mitochondria were enlarged and irregularly shaped, and showed signs of mitochondrial vacuolization, cristae swelling and a significant shift from tightly associated to loosely coupled ER-mitochondrial contacts. Hepatocytes from these livers also exhibited a substantial suppression of mitochondrial dynamics. Additionally, chronic alcohol feeding sensitized cultured hepatocytes and hepatocytes within the intact perfused liver to hormone dependent PI-PLC signaling. Acute alcohol treatment (25 mM) completely inhibited hormone-induced calcium increases in control livers, but not after chronic alcohol-feeding suggesting desensitization to the inhibitory actions of ethanol. Together these studies implicate chronic alcohol exposure in impairing intercellular Ca2+ signaling, mitochondrial quality, ER-mitochondrial structural-functional coupling and thereby disrupting liver homeostasis. Mitochondria can sequester large amounts of Ca2+ via the mitochondrial Ca2+ uniporter (MCU) and influence the spatiotemporal properties of cytosolic Ca 2+ signals through local feedback regulation of Ca2+ channels. Additionally, mitochondrial Ca2+ uptake has established roles in the regulation of energy homeostasis and cell death. The importance of mitochondrial calcium regulation is highlighted by the observation reported in our studies of the perinatal lethality of the MCU regulatory protein MICU1 deletion in mice. We further tested the impact of MICU1 loss under physiological stress using liver regeneration after partial hepatectomy (PHx) as a stress response model. Upon MICU1 loss, early priming is unaffected, but the pro-inflammatory phase does not resolve and liver regeneration fails, with impaired cell cycle entry and extensive necrosis post PHx. Ca2+ overload-induced mitochondrial permeability transition pore (PTP) opening is accelerated in MICU1-deficient hepatocytes. PTP inhibition prevents necrosis and rescues regeneration. Regulation of mitochondrial Ca2+ uptake through MICU1 is pivotal in protecting against Ca2+ overload to permit progression of liver regeneration