title: 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.
authors.affiliation: MitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors.forename: Anil Noronha
authors.initials: AN
authors.lastname: Antony
authors.affiliation: MitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors.forename: Melanie
authors.initials: M
authors.lastname: Paillard
authors.affiliation: MitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Moffat
authors.affiliation: MitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors.forename: Egle
authors.identifier: http://orcid.org/0000-0003-2635-9153
authors.initials: E
authors.lastname: Juskeviciute
authors.affiliation: MitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Correnti
authors.affiliation: Comparative Pathology and Mouse Phenotyping Shared Resource, College of Veterinary Medicine, Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Brad
authors.initials: B
authors.lastname: Bolon
authors.affiliation: MitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors.forename: Emanuel
authors.initials: E
authors.lastname: Rubin
authors.affiliation: MitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors.forename: György
authors.initials: G
authors.lastname: Csordás
authors.affiliation: MitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors.forename: Erin L
authors.initials: EL
authors.lastname: Seifert
authors.affiliation: MitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors.forename: Jan B
authors.initials: JB
authors.lastname: Hoek
authors.affiliation: MitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors.forename: György
authors.initials: G
authors.lastname: Hajnóczky
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival; D005260:Female; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000502:physiology; D008115:Liver Regeneration; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore
chemical_list: D002135:Calcium-Binding Proteins; C000610715:MICU1 protein, mouse; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D002118:Calcium