Abl2 kinase phosphorylates Bi-organellar regulator MNRR1 in mitochondria, stimulating respiration

Siddhesh Aras; Hassan Arrabi; Neeraja Purandare; Maik Hüttemann; John Kamholz; Stephan Züchner; Lawrence I Grossman

doi:10.1016/j.bbamcr.2016.11.029

Back

Abl2 kinase phosphorylates Bi-organellar regulator MNRR1 in mitochondria, stimulating respiration

Journal article

Open access

Peer reviewed

Abl2 kinase phosphorylates Bi-organellar regulator MNRR1 in mitochondria, stimulating respiration

Siddhesh Aras, Hassan Arrabi, Neeraja Purandare, Maik Hüttemann, John Kamholz, Stephan Züchner and Lawrence I Grossman

Biochimica et biophysica acta. Molecular cell research, Vol.1864(2), pp.440-448

02/2017

DOI: 10.1016/j.bbamcr.2016.11.029

PMID: 27913209

Files and links (1)

url

https://doi.org/10.1016/j.bbamcr.2016.11.029View

Published (Version of record) Open Access

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. •MNRR1 (CHCHD2) is a stress regulator functioning in both mitochondria and nucleus•In mitochondria MNRR1 binds to cytochrome c oxidase (COX)•Binding to COX is promoted by tyrosine phosphorylation•Phosphorylation is carried out by Abl2 kinase (ARG)•MNRR1 may be a modifier gene in a family with Charcot-Marie-Tooth disease type 1A

Abl2

Nucleus

Mitochondria

ABL tyrosine kinase

Transcription promoter

Phosphotyrosine

Details

Title: Subtitle: Abl2 kinase phosphorylates Bi-organellar regulator MNRR1 in mitochondria, stimulating respiration
Creators: Siddhesh Aras - Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA
Hassan Arrabi - Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA
Neeraja Purandare - Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA
Maik Hüttemann - Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA
John Kamholz - Department of Neurology, University of Iowa Carver School of Medicine, Iowa City, IA 52242, USA
Stephan Züchner - Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL 33136, USA
Lawrence I Grossman - Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA
Resource Type: Journal article
Publication Details: Biochimica et biophysica acta. Molecular cell research, Vol.1864(2), pp.440-448
DOI: 10.1016/j.bbamcr.2016.11.029
PMID: 27913209
NLM abbreviation: Biochim Biophys Acta Mol Cell Res
ISSN: 0167-4889
eISSN: 1879-2596
Publisher: Elsevier B.V
Grant note: W81XWH-16-1-0516 / Peer Reviewed Medical Research Program Henry L. Brasza endowment
Language: English
Date published: 02/2017
Academic Unit: Neurology; Psychiatry
Record Identifier: 9984020635102771

Metrics

25 Record Views

27 Times Cited - Web of Science