title: Abl2 kinase phosphorylates Bi-organellar regulator MNRR1 in mitochondria, stimulating respiration.
abstract: We previously showed that MNRR1 (Mitochondrial Nuclear Retrograde Regulator 1, also CHCHD2) functions in two subcellular compartments, displaying a different function in each. In the mitochondria it is a stress regulator of respiration that binds to cytochrome c oxidase (COX) whereas in the nucleus it is a transactivator of COX4I2 and other hypoxia-stimulated genes. We now show that binding of MNRR1 to COX is promoted by phosphorylation at tyrosine-99 and that this interaction stimulates respiration. We show that phosphorylation of MNRR1 takes place in mitochondria and is mediated by Abl2 kinase (ARG). A family with Charcot-Marie-Tooth disease type 1A with an exaggerated phenotype harbors a Q112H mutation in MNRR1, located in a domain that is necessary for transcriptional activation by MNRR1. Furthermore, the mutation causes the protein to function suboptimally in the mitochondria in response to cellular stress. The Q112H mutation hinders the ability of the protein to interact with Abl kinase, leading to defective tyrosine phosphorylation and a resultant defect in respiration.
authors.affiliation: Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Siddhesh
authors.initials: S
authors.lastname: Aras
authors.affiliation: Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Hassan
authors.initials: H
authors.lastname: Arrabi
authors.affiliation: Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Neeraja
authors.initials: N
authors.lastname: Purandare
authors.affiliation: Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Maik
authors.initials: M
authors.lastname: Hüttemann
authors.affiliation: Department of Neurology, University of Iowa Carver School of Medicine, Iowa City, IA 52242, USA.
authors.forename: John
authors.initials: J
authors.lastname: Kamholz
authors.affiliation: Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Stephan
authors.initials: S
authors.lastname: Züchner
authors.affiliation: Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA. Electronic address: l.grossman@wayne.edu.
authors.forename: Lawrence I
authors.initials: LI
authors.lastname: Grossman
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D002460:Cell Line; D019069:Cell Respiration; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics; D004268:DNA-Binding Proteins; D005260:Female; D006801:Humans; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D010085:Oxidative Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: C580880:CHCHD2 protein, human; D004268:DNA-Binding Proteins; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D000255:Adenosine Triphosphate; C426236:ARG tyrosine kinase; D011505:Protein-Tyrosine Kinases
keywords: ABL tyrosine kinase; Abl2; Mitochondria; Nucleus; Phosphotyrosine; Transcription promoter