title: Metalloprotease OMA1 Fine-tunes Mitochondrial Bioenergetic Function and Respiratory Supercomplex Stability.
abstract: Mitochondria are involved in key cellular functions including energy production, metabolic homeostasis, and apoptosis. Normal mitochondrial function is preserved by several interrelated mechanisms. One mechanism - intramitochondrial quality control (IMQC) - is represented by conserved proteases distributed across mitochondrial compartments. Many aspects and physiological roles of IMQC components remain unclear. Here, we show that the IMQC protease Oma1 is required for the stability of the respiratory supercomplexes and thus balanced and tunable bioenergetic function. Loss of Oma1 activity leads to a specific destabilization of respiratory supercomplexes and consequently to unbalanced respiration and progressive respiratory decline in yeast. Similarly, experiments in cultured Oma1-deficient mouse embryonic fibroblasts link together impeded supercomplex stability and inability to maintain proper respiration under conditions that require maximal bioenergetic output. Finally, transient knockdown of OMA1 in zebrafish leads to impeded bioenergetics and morphological defects of the heart and eyes. Together, our biochemical and genetic studies in yeast, zebrafish and mammalian cells identify a novel and conserved physiological role for Oma1 protease in fine-tuning of respiratory function. We suggest that this unexpected physiological role is important for cellular bioenergetic plasticity and may contribute to Oma1-associated disease phenotypes in humans.
authors.affiliation: Department of Biochemistry.|Redox Biology Center and.
authors.forename: Iryna
authors.initials: I
authors.lastname: Bohovych
authors.affiliation: Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Mario R
authors.initials: MR
authors.lastname: Fernandez
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Rahn
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Krista D
authors.initials: KD
authors.lastname: Stackley
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Bestman
authors.affiliation: Redox Biology Center and.|School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln NE, 68588, USA.
authors.forename: Annadurai
authors.initials: A
authors.lastname: Anandhan
authors.affiliation: Redox Biology Center and.|School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln NE, 68588, USA.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Franco
authors.affiliation: Department of Physiology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Claypool
authors.affiliation: Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Lewis
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Sherine S L
authors.initials: SS
authors.lastname: Chan
authors.affiliation: Department of Biochemistry.|Redox Biology Center and.
authors.forename: Oleh
authors.initials: O
authors.lastname: Khalimonchuk
mesh_terms: D000818:Animals; D002460:Cell Line; D004625:Embryo, Nonmammalian / Q000187:drug effects / Q000378:metabolism; D004734:Energy Metabolism; D007814:Larva / Q000378:metabolism; D045726:Metalloproteases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D060172:Morpholinos / Q000494:pharmacology; D010641:Phenotype; D055550:Protein Stability; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish / Q000254:growth & development / Q000378:metabolism; D029961:Zebrafish Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D024101:Mitochondrial Proteins; D060172:Morpholinos; D034741:RNA, Small Interfering; D029701:Saccharomyces cerevisiae Proteins; D029961:Zebrafish Proteins; D045726:Metalloproteases; C572960:OMA1 protein, mouse