PMID:22228767

Citation	An, J, Shi, J, He, Q, Lui, K, Liu, Y, Huang, Y and Sheikh, MS (2012) CHCM1/CHCHD6, novel mitochondrial protein linked to regulation of mitofilin and mitochondrial cristae morphology. J. Biol. Chem. 287:7411-26
Abstract	The structural integrity of mitochondrial cristae is crucial for mitochondrial functions; however, the molecular events controlling the structural integrity and biogenesis of mitochondrial cristae remain to be fully elucidated. Here, we report the functional characterization of a novel mitochondrial protein named CHCM1 (coiled coil helix cristae morphology 1)/CHCHD6. CHCM1/CHCHD6 harbors a coiled coil helix-coiled coil helix domain at its C-terminal end and predominantly localizes to mitochondrial inner membrane. CHCM1/CHCHD6 knockdown causes severe defects in mitochondrial cristae morphology. The mitochondrial cristae in CHCM1/CHCHD6-deficient cells become hollow with loss of structural definitions and reduction in electron-dense matrix. CHCM1/CHCHD6 depletion also leads to reductions in cell growth, ATP production, and oxygen consumption. CHCM1/CHCHD6 through its C-terminal end strongly and directly interacts with the mitochondrial inner membrane protein mitofilin, which is known to also control mitochondrial cristae morphology. CHCM1/CHCHD6 also interacts with other mitofilin-associated proteins, including DISC1 and CHCHD3. Knockdown of CHCM1/CHCHD6 reduces mitofilin protein levels; conversely, mitofilin knockdown leads to reduction in CHCM1 levels, suggesting coordinate regulation between these proteins. Our results further indicate that genotoxic anticancer drugs that induce DNA damage down-regulate CHCM1/CHCHD6 expression in multiple human cancer cells, whereas mitochondrial respiratory chain inhibitors do not affect CHCM1/CHCHD6 levels. CHCM1/CHCHD6 knockdown in human cancer cells enhances chemosensitivity to genotoxic anticancer drugs, whereas its overexpression increases resistance. Collectively, our results indicate that CHCM1/CHCHD6 is linked to regulation of mitochondrial cristae morphology, cell growth, ATP production, and oxygen consumption and highlight its potential as a possible target for cancer therapeutics.
Links	PubMed PMC3293568 Online version:10.1074/jbc.M111.277103
Keywords	Adenosine Triphosphate/biosynthesis; Adenosine Triphosphate/genetics; Amino Acid Sequence; Antineoplastic Agents/pharmacology; Cell Line, Tumor; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Mitochondria/genetics; Mitochondria/metabolism; Mitochondria/pathology; Mitochondrial Membranes/metabolism; Mitochondrial Membranes/pathology; Mitochondrial Proteins/biosynthesis; Mitochondrial Proteins/genetics; Mitochondrial Proteins/metabolism; Molecular Sequence Data; Muscle Proteins/biosynthesis; Muscle Proteins/genetics; Neoplasm Proteins/genetics; Neoplasm Proteins/metabolism; Neoplasms/drug therapy; Neoplasms/genetics; Neoplasms/metabolism; Neoplasms/pathology; Nerve Tissue Proteins/genetics; Nerve Tissue Proteins/metabolism; Oxygen Consumption/drug effects; Oxygen Consumption/genetics; Protein Structure, Tertiary
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:MIC60	enables	GO:0005515: protein binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:Q9BRQ6	F		Seeded From UniProt	complete
HUMAN:MIC25	located_in	GO:0005743: mitochondrial inner membrane	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
HUMAN:MIC25	involved_in	GO:0006974: cellular response to DNA damage stimulus	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:MIC25	located_in	GO:0005739: mitochondrion	ECO:0000315: mutant phenotype evidence used in manual assertion		C		Seeded From UniProt	complete
HUMAN:MIC25	involved_in	GO:0042407: cristae formation	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:MIC25	enables	GO:0005515: protein binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:Q16891	F		Seeded From UniProt	complete
HUMAN:MIC25	enables	GO:0005515: protein binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:Q9NRI5	F		Seeded From UniProt	complete
HUMAN:MIC25	enables	GO:0005515: protein binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:Q9NX63	F		Seeded From UniProt	complete
HUMAN:DISC1	enables	GO:0005515: protein binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:Q9BRQ6	F		Seeded From UniProt	complete
HUMAN:MIC19	enables	GO:0005515: protein binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:Q9BRQ6	F		Seeded From UniProt	complete

References

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