MICU1 regulation of mitochondrial Ca(2+) uptake dictates survival and tissue regeneration.

Anil Noronha Antony,Emanuel Rubin,Erin L Seifert,Cynthia Moffat,György Csordás,Jason Correnti,Egle Juskeviciute,Melanie Paillard,Brad Bolon,Jan B Hoek,György Hajnóczky

doi:10.1038/ncomms10955

Anil Noronha Antony, Emanuel Rubin + Show 9 more

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https://doi.org/10.1038/ncomms10955

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Abstract

Mitochondrial Ca2+ uptake through the recently discovered Mitochondrial Calcium Uniporter (MCU) is controlled by its gatekeeper Mitochondrial Calcium Uptake 1 (MICU1). However, the physiological and pathological role of MICU1 remains unclear. Here we show that MICU1 is vital for adaptation to postnatal life and for tissue repair after injury. MICU1 knockout is perinatally lethal in mice without causing gross anatomical defects. We used liver regeneration after partial hepatectomy as a physiological 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. Ca2+ overload-induced mitochondrial permeability transition pore (PTP) opening is accelerated in MICU1-deficient hepatocytes. PTP inhibition prevents necrosis and rescues regeneration. Thus, our study identifies an unanticipated dependence of liver regeneration on MICU1 and highlights the importance of regulating MCU under stress conditions when the risk of Ca2+ overload is elevated.

Highlights

Mitochondrial Ca2 þ uptake through the recently discovered Mitochondrial Calcium Uniporter (MCU) is controlled by its gatekeeper Mitochondrial Calcium Uptake 1 (MICU1)
The currently available results do not provide a coherent picture on the physiological relevance of MCU, at least some laboratory mouse strains seem to be able to cope with the loss of mitochondrial Ca2 þ uptake and show functional impairment only when adaptation is needed to meet an abrupt increase in tissue energy needs
The liver is an organ of particular interest because [Ca2 þ ]c signals are central to stimulation of metabolism as well as for stress responses, and both decoding of [Ca2 þ ]c oscillations by mitochondria and protection of mitochondria from calcium overload depend on MICU1 in isolated hepatocytes[8,19]

Summary

Introduction

Mitochondrial Ca2 þ uptake through the recently discovered Mitochondrial Calcium Uniporter (MCU) is controlled by its gatekeeper Mitochondrial Calcium Uptake 1 (MICU1). It is of interest to determine the in vivo role of MICU1, which in cultured cells can both suppress and enhance MCU-mediated Ca2 þ uptake dependent on [Ca2 þ ]c In this regard, the liver is an organ of particular interest because [Ca2 þ ]c signals are central to stimulation of metabolism as well as for stress responses, and both decoding of [Ca2 þ ]c oscillations by mitochondria and protection of mitochondria from calcium overload depend on MICU1 in isolated hepatocytes[8,19]. Our data in MICU1-deficient mice reveal that the tight Ca2 þ -dependent control of mitochondrial Ca2 þ uptake is essential for survival under acute stress conditions and to allow a well-integrated tissue repair response, highlighting the critical role of MICU1 in physiological and pathological conditions

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