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

Abstract:

:Mitochondrial Ca(2+) 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. Ca(2+) 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 Ca(2+) overload is elevated.

journal_name

Nat Commun

journal_title

Nature communications

authors

Antony AN,Paillard M,Moffat C,Juskeviciute E,Correnti J,Bolon B,Rubin E,Csordás G,Seifert EL,Hoek JB,Hajnóczky G

doi

10.1038/ncomms10955

subject

Has Abstract

pub_date

2016-03-09 00:00:00

pages

10955

issn

2041-1723

pii

ncomms10955

journal_volume

7

pub_type

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