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Biochim Biophys Acta Mol Cell Res. 2017 Feb;1864(2):440-448. doi: 10.1016/j.bbamcr.2016.11.029. Epub 2016 Nov 30.

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

Author information

1
Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA.
2
Department of Neurology, University of Iowa Carver School of Medicine, Iowa City, IA 52242, USA.
3
Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
4
Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA. Electronic address: l.grossman@wayne.edu.

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.

KEYWORDS:

ABL tyrosine kinase; Abl2; Mitochondria; Nucleus; Phosphotyrosine; Transcription promoter

PMID:
27913209
DOI:
10.1016/j.bbamcr.2016.11.029
[Indexed for MEDLINE]
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