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Mitochondrion. 2015 Jan;20:43-51. doi: 10.1016/j.mito.2014.10.003. Epub 2014 Oct 12.

MNRR1 (formerly CHCHD2) is a bi-organellar regulator of mitochondrial metabolism.

Author information

1
Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201 USA.
2
Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201 USA; College of Medicine, Dankook University, Cheonan-si, Chungcheongnam-do 330-714, Republic of Korea.
3
Medical Research Council Mitochondrial Biology Unit, Wellcome Trust, MRC Building, Hills Road, Cambridge CB2 0XY, UK.
4
Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201 USA; Cardiovascular Research Institute, Wayne State University, Detroit, MI 48201, USA.
5
Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201 USA; Cardiovascular Research Institute, Wayne State University, Detroit, MI 48201, USA. Electronic address: lgrossman@wayne.edu.

Abstract

Our understanding of stress-associated regulatory mechanisms for mitochondria remains incomplete. We now report a new regulator of mitochondrial metabolism, the coiled-coil-helix-coiled-coil-helix domain-containing protein 2 (CHCHD2) which, based on the functionality described here, is renamed MNRR1 (Mitochondria Nuclear Retrograde Regulator 1). It functions in a novel way by acting in two cellular compartments, mitochondria and nucleus. In normally growing cells most MNRR1 is located in mitochondria; during stress most MNRR1 is now located in the nucleus. MNRR1 is imported to the mitochondrial intermembrane space by a Mia40-mediated pathway, where it binds to cytochrome c oxidase (COX). This association is required for full COX activity. Decreased MNRR1 levels produce widespread dysfunction including reduced COX activity, membrane potential, and growth rate, and increased reactive oxygen species and mitochondrial fragmentation. In the nucleus, MNRR1 acts as a transcription factor, one of whose targets is the COX subunit 4 isoform, COX4I2, which is transcriptionally stimulated by hypoxia. This MNRR1-mediated stress response may provide an important survival mechanism for cells under conditions of oxidative or hypoxic stress, both in the acute phase by altering mitochondrial oxygen utilization and in the chronic phase by promoting COX remodeling.

KEYWORDS:

COX4I2; Hypoxia; Mitochondria; Stress

PMID:
25315652
DOI:
10.1016/j.mito.2014.10.003
[Indexed for MEDLINE]

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