Abstract
CX.sub.9C proteins: Stress-responsive IMS regulators and disease modifiers
Mitochondrion, Vol.24, p.S23-S24
09/01/2015
DOI: 10.1016/j.mito.2015.07.069
Abstract
CX9C proteins, which adopt a coiled coil–helix–coiled coil–helix (CHCH) fold stabilized by two disulfide bonds, are typically found in the mitochondrial intermembrane space. We have discovered that two members of this family, CHCHD2 (MNRR1) and CHCHD10, are mitochondrial stress-responsive regulators that are physically bound to cytochrome c oxidase (COX) within the mitochondria and also serve as modulators of transcription in the nucleus. CHCHD2 (MNRR1) interacts with and activates a novel oxygen responsive element (ORE) in the promoter for COX4I2, maximally at an oxygen tension of 4%. The conserved ORE was also found in the MNRR1 promoter, which thus regulates its own transactivation. In addition to COX4I2 and itself, MNRR1 could function as a hypoxic transactivator for other genes that harbor the novel conserved ORE in their promoters such as SOD2, ATG7, and NDUFS3, the levels of which are lowered in cells deficient in MNRR1. Cells with increased levels of MNRR1 show increased oxygen consumption and cells with reduced levels of MNRR1 (KD cells) show reduced oxygen consumption; KD cells also show increased ROS production, reduced growth rate and fragmented mitochondria. MNRR1 requires phosphorylation at Tyr-99, carried out in vivo by Abl kinase, for efficient binding to COX; cells containing the Y99F replacement show the phenotype of KD cells. A related CX9C protein, CHCHD10, is also present in both the mitochondria and the nucleus. In the mitochondria it also binds to COX and also causes increased oxygen consumption; furthermore, it interacts with MNRR1. A family with a severe form of Charcot-Marie-Tooth (CMT) disease type 1A, caused by a duplication of PMP22, also carries a Q112H mutation in MNRR1. This mutation reduces the ability of Abl kinase to bind to MNRR1 and to phosphorylate it at Y99, and it reduces the ability of MNRR1 to bind to COX and to promote transcription of a COX4I2 reporter. This mutation thus represents a modifier gene whereby a reduction of mitochondrial function can exacerbate the phenotype of a non-mitochondrial disease mutation.
Details
- Title: Subtitle
- CX.sub.9C proteins: Stress-responsive IMS regulators and disease modifiers
- Creators
- Siddhesh ArasHassan ArrabiNeeraja PunandareStephan ZuchnerJohn KamholzMaik HuttemannLawrence I Grossman
- Resource Type
- Abstract
- Publication Details
- Mitochondrion, Vol.24, p.S23-S24
- Publisher
- Elsevier B.V
- DOI
- 10.1016/j.mito.2015.07.069
- ISSN
- 1567-7249
- eISSN
- 1872-8278
- Language
- English
- Date published
- 09/01/2015
- Description audience
- Academic
- Academic Unit
- Psychiatry; Neurology
- Record Identifier
- 9984020994302771
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