MICU1 regulation of mitochondrial Ca2+ uptake dictates survival and tissue regeneration

Anil Noronha Antony, Melanie Paillard, Cynthia Moffat, Egle Juskeviciute, Jason Correnti, Brad Bolon, Emanuel Rubin, György Csordás, Erin L. Seifert (), Jan B. Hoek () and György Hajnóczky ()
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Anil Noronha Antony: MitoCare Center, Anatomy and Cell Biology, Thomas Jefferson University
Melanie Paillard: MitoCare Center, Anatomy and Cell Biology, Thomas Jefferson University
Cynthia Moffat: MitoCare Center, Anatomy and Cell Biology, Thomas Jefferson University
Egle Juskeviciute: MitoCare Center, Anatomy and Cell Biology, Thomas Jefferson University
Jason Correnti: MitoCare Center, Anatomy and Cell Biology, Thomas Jefferson University
Brad Bolon: Comparative Pathology and Mouse Phenotyping Shared Resource, College of Veterinary Medicine, Ohio State University
Emanuel Rubin: MitoCare Center, Anatomy and Cell Biology, Thomas Jefferson University
György Csordás: MitoCare Center, Anatomy and Cell Biology, Thomas Jefferson University
Erin L. Seifert: MitoCare Center, Anatomy and Cell Biology, Thomas Jefferson University
Jan B. Hoek: MitoCare Center, Anatomy and Cell Biology, Thomas Jefferson University
György Hajnóczky: MitoCare Center, Anatomy and Cell Biology, Thomas Jefferson University

Nature Communications, 2016, vol. 7, issue 1, 1-10

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms10955

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