title: OPA1-dependent cristae modulation is essential for cellular adaptation to metabolic demand.
abstract: Cristae, the organized invaginations of the mitochondrial inner membrane, respond structurally to the energetic demands of the cell. The mechanism by which these dynamic changes are regulated and the consequences thereof are largely unknown. Optic atrophy 1 (OPA1) is the mitochondrial GTPase responsible for inner membrane fusion and maintenance of cristae structure. Here, we report that OPA1 responds dynamically to changes in energetic conditions to regulate cristae structure. This cristae regulation is independent of OPA1's role in mitochondrial fusion, since an OPA1 mutant that can still oligomerize but has no fusion activity was able to maintain cristae structure. Importantly, OPA1 was required for resistance to starvation-induced cell death, for mitochondrial respiration, for growth in galactose media and for maintenance of ATP synthase assembly, independently of its fusion activity. We identified mitochondrial solute carriers (SLC25A) as OPA1 interactors and show that their pharmacological and genetic blockade inhibited OPA1 oligomerization and function. Thus, we propose a novel way in which OPA1 senses energy substrate availability, which modulates its function in the regulation of mitochondrial architecture in a SLC25A protein-dependent manner.
authors.affiliation: Department of Cellular & Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
authors.forename: David A
authors.initials: DA
authors.lastname: Patten
authors.affiliation: Department of Cellular & Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Jacob
authors.initials: J
authors.lastname: Wong
authors.affiliation: Department of Cellular & Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Mireille
authors.initials: M
authors.lastname: Khacho
authors.affiliation: Montreal Neurological Institute, McGill University, Montreal, QC, Canada.
authors.forename: Vincent
authors.initials: V
authors.lastname: Soubannier
authors.affiliation: Department of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Mailloux
authors.affiliation: Department of Cellular & Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Karine
authors.initials: K
authors.lastname: Pilon-Larose
authors.affiliation: Department of Cellular & Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Jason G
authors.initials: JG
authors.lastname: MacLaurin
authors.affiliation: Department of Cellular & Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
authors.forename: David S
authors.initials: DS
authors.lastname: Park
authors.affiliation: Montreal Neurological Institute, McGill University, Montreal, QC, Canada.
authors.forename: Heidi M
authors.initials: HM
authors.lastname: McBride
authors.affiliation: Department of Cellular & Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Laura
authors.initials: L
authors.lastname: Trinkle-Mulcahy
authors.affiliation: Department of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Mary-Ellen
authors.initials: ME
authors.lastname: Harper
authors.affiliation: Département de Biologie Médicale, Université du Québec à Trois-Rivières, Trois-Rivières, QC, Canada rslack@uottawa.ca marc.germain1@uqtr.ca.
authors.forename: Marc
authors.initials: M
authors.lastname: Germain
authors.affiliation: Department of Cellular & Molecular Medicine, University of Ottawa, Ottawa, ON, Canada rslack@uottawa.ca marc.germain1@uqtr.ca.
authors.forename: Ruth S
authors.initials: RS
authors.lastname: Slack
mesh_terms: D000818:Animals; D027321:Anion Transport Proteins / Q000235:genetics / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000201:enzymology* / Q000648:ultrastructure; D063154:Mitochondrial Dynamics / Q000502:physiology*; D051336:Mitochondrial Membranes / Q000201:enzymology* / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D010101:Oxygen Consumption / Q000502:physiology; D055503:Protein Multimerization / Q000502:physiology
chemical_list: D027321:Anion Transport Proteins; D024101:Mitochondrial Proteins; D020558:GTP Phosphohydrolases; C415198:OPA1 protein, human; C498809:Opa1 protein, mouse
keywords: ATP synthase; OPA1; SLC25A; cristae; mitochondria