MICU1 Regulation of Mitochondrial Calcium Uptake is Crucial for Liver Regeneration

Abstract

Liver regeneration is a complex and well-orchestrated process where after partial hepatectomy (PHx) the initial mass of the organ is restored through both proliferative and hepatoprotective signaling cascades. Among the myriad of agonists that drives this process many involve Ca2+ signaling. Mechanisms through which cytosolic and mitochondrial Ca2+ signaling impact the onset of regeneration and progression of hepatocytes through the cell cycle are not well understood. Mitochondrial Ca2+ handling is critical in maintaining cellular Ca2+ homeostasis. MICU1 (mitochondrial calcium uptake-1) has been identified as a critical regulatory protein of MCU (mitochondrial calcium uniporter) mediated Ca2+ uptake. Here we test the hypothesis that deregulation of mitochondrial Ca2+ transport by knockdown (KD) of MICU1 compromises liver regeneration. We performed 70% PHX in mice with acute liver-specific MICU1 deletion. By 30hrs post-PHX, KD mice showed evidence of major liver damage and impaired function as shown by liver histology and dramatic increases in serum ALT and bilirubin as compared to control. Hepatocyte proliferation as measured by BrdU incorporation was undetectable in remnant livers in KD mice. This correlated with a total lack of cyclin D1 expression 30hrs post-PHX. Events associated with the early priming phase (1hr) of regeneration were mostly unaffected by the loss of MICU1. However, a sustained tissue IL6 and TNFα elevation in KD mice by 6hrs suggested a failure to resolve early pro-inflammatory responses. Experiments on isolated hepatocytes indicate that MICU1 ablation decreases the mitochondrial Ca2+ uptake threshold and enhances their susceptibility to permeability transition due to calcium overload. Treatment with the PTP inhibitor NIM811 protected KD mice from liver damage and restored hepatocyte proliferation after PHX. In summary, regulation of mitochondrial calcium uptake through MICU1 is pivotal in protecting against mitochondrial calcium overload to permit progression of liver regeneration.