title: A Mitofusin-2-dependent inactivating cleavage of Opa1 links changes in mitochondria cristae and ER contacts in the postprandial liver.
abstract: Hepatic metabolism requires mitochondria to adapt their bioenergetic and biosynthetic output to accompany the ever-changing anabolic/catabolic state of the liver cell, but the wiring of this process is still largely unknown. Using a postprandial mouse liver model and quantitative cryo-EM analysis, we show that when the hepatic mammalian target of rapamycin complex 1 (mTORC1) signaling pathway disengages, the mitochondria network fragments, cristae density drops by 30%, and mitochondrial respiratory capacity decreases by 20%. Instead, mitochondria-ER contacts (MERCs), which mediate calcium and phospholipid fluxes between these organelles, double in length. These events are associated with the transient expression of two previously unidentified C-terminal fragments (CTFs) of Optic atrophy 1 (Opa1), a mitochondrial GTPase that regulates cristae biogenesis and mitochondria dynamics. Expression of Opa1 CTFs in the intermembrane space has no effect on mitochondria morphology, supporting a model in which they are intermediates of an Opa1 degradation program. Using an in vitro assay, we show that these CTFs indeed originate from the cleavage of Opa1 at two evolutionarily conserved consensus sites that map within critical folds of the GTPase. This processing of Opa1, termed C-cleavage, is mediated by the activity of a cysteine protease whose activity is independent from that of Oma1 and presenilin-associated rhomboid-like (PARL), two known Opa1 regulators. However, C-cleavage requires Mitofusin-2 (Mfn2), a key factor in mitochondria-ER tethering, thereby linking cristae remodeling to MERC assembly. Thus, in vivo, mitochondria adapt to metabolic shifts through the parallel remodeling of the cristae and of the MERCs via a mechanism that degrades Opa1 in an Mfn2-dependent pathway.
authors.affiliation: Department of Molecular Biology, Medical Biochemistry and Pathology, Université Laval, Quebec, Canada G1V 0A6; Mitochondria Biology Laboratory, Centre de recherche de l'Institut universitaire en santé mentale de Québec, Quebec City, QC, Canada G1J 2G3;
authors.forename: Aditi
authors.initials: A
authors.lastname: Sood
authors.affiliation: Department of Molecular Biology, Medical Biochemistry and Pathology, Université Laval, Quebec, Canada G1V 0A6; Mitochondria Biology Laboratory, Centre de recherche de l'Institut universitaire en santé mentale de Québec, Quebec City, QC, Canada G1J 2G3;
authors.forename: Danny Vijey
authors.initials: DV
authors.lastname: Jeyaraju
authors.affiliation: Montreal Neurological Institute, McGill University, Montreal, Canada H3A 2B4;
authors.forename: Julien
authors.initials: J
authors.lastname: Prudent
authors.affiliation: Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, Quebec City, QC, Canada, G1V 4G5; and.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Caron
authors.affiliation: Mitochondria Biology Laboratory, Centre de recherche de l'Institut universitaire en santé mentale de Québec, Quebec City, QC, Canada G1J 2G3;
authors.forename: Philippe
authors.initials: P
authors.lastname: Lemieux
authors.affiliation: Montreal Neurological Institute, McGill University, Montreal, Canada H3A 2B4;
authors.forename: Heidi May
authors.initials: HM
authors.lastname: McBride
authors.affiliation: Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, Quebec City, QC, Canada, G1V 4G5; and.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Laplante
authors.affiliation: Department of Psychiatry and Neurosciences, Université Laval, Quebec, Canada G1V 0A6.
authors.forename: Katalin
authors.initials: K
authors.lastname: Tóth
authors.affiliation: Department of Molecular Biology, Medical Biochemistry and Pathology, Université Laval, Quebec, Canada G1V 0A6; Mitochondria Biology Laboratory, Centre de recherche de l'Institut universitaire en santé mentale de Québec, Quebec City, QC, Canada G1J 2G3; luca.pellegrini@fmed.ulaval.ca.
authors.forename: Luca
authors.initials: L
authors.lastname: Pellegrini
mesh_terms: D000818:Animals; D020013:Calcium Signaling / Q000502:physiology*; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D045726:Metalloproteases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008930:Mitochondria, Liver / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D019518:Postprandial Period / Q000502:physiology*; D059748:Proteolysis; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D024101:Mitochondrial Proteins; D046912:Multiprotein Complexes; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D045726:Metalloproteases; C572960:OMA1 protein, mouse; D020558:GTP Phosphohydrolases; C488751:Mfn2 protein, mouse; C498809:Opa1 protein, mouse
keywords: Mfn2; Opa1; mTORC1; mitochondria; mitochondria–ER contacts