title: MCJ/DnaJC15, an endogenous mitochondrial repressor of the respiratory chain that controls metabolic alterations.
abstract: Mitochondria are the main engine that generates ATP through oxidative phosphorylation within the respiratory chain. Mitochondrial respiration is regulated according to the metabolic needs of cells and can be modulated in response to metabolic changes. Little is known about the mechanisms that regulate this process. Here, we identify MCJ/DnaJC15 as a distinct cochaperone that localizes at the mitochondrial inner membrane, where it interacts preferentially with complex I of the electron transfer chain. We show that MCJ impairs the formation of supercomplexes and functions as a negative regulator of the respiratory chain. The loss of MCJ leads to increased complex I activity, mitochondrial membrane potential, and ATP production. Although MCJ is dispensable for mitochondrial function under normal physiological conditions, MCJ deficiency affects the pathophysiology resulting from metabolic alterations. Thus, enhanced mitochondrial respiration in the absence of MCJ prevents the pathological accumulation of lipids in the liver in response to both fasting and a high-cholesterol diet. Impaired expression or loss of MCJ expression may therefore result in a "rapid" metabolism that mitigates the consequences of metabolic disorders.
authors.affiliation: Department of Medicine, University of Vermont, Burlington, VT, USA.
authors.forename: Ketki M
authors.initials: KM
authors.lastname: Hatle
authors.forename: Phani
authors.initials: P
authors.lastname: Gummadidala
authors.forename: Nicolás
authors.initials: N
authors.lastname: Navasa
authors.forename: Edgar
authors.initials: E
authors.lastname: Bernardo
authors.forename: John
authors.initials: J
authors.lastname: Dodge
authors.forename: Brian
authors.initials: B
authors.lastname: Silverstrim
authors.forename: Karen
authors.initials: K
authors.lastname: Fortner
authors.forename: Elianne
authors.initials: E
authors.lastname: Burg
authors.forename: Benajamin T
authors.initials: BT
authors.lastname: Suratt
authors.forename: Juergen
authors.initials: J
authors.lastname: Hammer
authors.forename: Michael
authors.initials: M
authors.lastname: Radermacher
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Taatjes
authors.forename: Tina
authors.initials: T
authors.lastname: Thornton
authors.forename: Juan
authors.initials: J
authors.lastname: Anguita
authors.forename: Mercedes
authors.initials: M
authors.lastname: Rincon
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D019069:Cell Respiration / Q000235:genetics; D002784:Cholesterol / Q000009:adverse effects; D004032:Diet; D042967:Electron Transport Complex I / Q000235:genetics / Q000378:metabolism*; D005234:Fatty Liver / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism*; D018832:Molecular Chaperones / Q000235:genetics* / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D012402:Rotenone / Q000494:pharmacology
chemical_list: C519405:DNAJC15 protein, human; D050956:HSP40 Heat-Shock Proteins; C582292:Mcj protein, mouse; D024101:Mitochondrial Proteins; D018832:Molecular Chaperones; D012097:Repressor Proteins; D012402:Rotenone; D000255:Adenosine Triphosphate; D002784:Cholesterol; D042967:Electron Transport Complex I