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PMID:22228767

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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

Significance

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


See also

References

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