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PMID:15044455

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Citation

Guo, Y, Cheong, N, Zhang, Z, De Rose, R, Deng, Y, Farber, SA, Fernandes-Alnemri, T and Alnemri, ES (2004) Tim50, a component of the mitochondrial translocator, regulates mitochondrial integrity and cell death. J. Biol. Chem. 279:24813-25

Abstract

In yeast, Tim50 along with Tim23 regulate translocation of presequence-containing proteins across the mitochondrial inner membrane. Here, we describe the identification and characterization of a novel human mitochondrial inner membrane protein homologous to the yeast Tim50. We demonstrate that human Tim50 possesses phosphatase activity and is present in a complex with human Tim23. Down-regulation of human Tim50 expression by RNA interference increases the sensitivity of human cell lines to death stimuli by accelerating the release of cytochrome c from the mitochondria. Furthermore, injection of Tim50-specific morpholino antisense oligonucleotides during early zebrafish embryonic development causes neurodegeneration, dysmorphic hearts, and reduced motility as a result of increased cell death. These observations indicate that loss of Tim50 in vertebrates causes mitochondrial membrane permeabilization and dysfunction followed by cytoplasmic release of cytochrome c along with other mitochondrial inducers of cell death. Thus Tim50 is important for both mitochondrial function and early neuronal development.

Links

PubMed Online version:10.1074/jbc.M402049200

Keywords

Acridine Orange/pharmacology; Amino Acid Sequence; Animals; Apoptosis; Carrier Proteins/chemistry; Carrier Proteins/physiology; Cell Death; Cell Line; Cell Line, Tumor; Cell Membrane/metabolism; Cytochromes c/metabolism; DNA, Complementary/metabolism; Down-Regulation; Genetic Vectors; Humans; Hydrogen-Ion Concentration; Immunoblotting; In Situ Hybridization; Membrane Proteins/chemistry; Membrane Proteins/physiology; Membrane Transport Proteins/chemistry; Membrane Transport Proteins/physiology; Mice; Microscopy, Fluorescence; Mitochondria/metabolism; Mitochondrial Membrane Transport Proteins; Molecular Sequence Data; Neurons/metabolism; Oligonucleotides/chemistry; Precipitin Tests; Protein Binding; Protein Conformation; Protein Structure, Tertiary; RNA Interference; RNA, Small Interfering/metabolism; Saccharomyces cerevisiae Proteins/chemistry; Saccharomyces cerevisiae Proteins/physiology; Sequence Homology, Amino Acid; Staurosporine/pharmacology; Subcellular Fractions; Substrate Specificity; Tissue Distribution; Transfection; Trypsin/chemistry; Trypsin/pharmacology; Two-Hybrid System Techniques; Ultraviolet Rays; Zebrafish

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:TIM23

located_in

GO:0005758: mitochondrial intermembrane space

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:TIM23

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q3ZCQ8

F

Seeded From UniProt

complete

HUMAN:HTRA2

located_in

GO:0005758: mitochondrial intermembrane space

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:TIM50

acts_upstream_of_or_within

GO:0001836: release of cytochrome c from mitochondria

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TIM50

enables

GO:0004721: phosphoprotein phosphatase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:TIM50

enables

GO:0005134: interleukin-2 receptor binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:TIM50

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O14925

F

Seeded From UniProt

complete

HUMAN:TIM50

involved_in

GO:0007006: mitochondrial membrane organization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TIM50

involved_in

GO:0006470: protein dephosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TIM50

enables

GO:0004722: protein serine/threonine phosphatase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:TIM50

enables

GO:0004725: protein tyrosine phosphatase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:TIM50

located_in

GO:0005743: mitochondrial inner membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:TIM50

part_of

GO:0005744: TIM23 mitochondrial import inner membrane translocase complex

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O14925

C

Seeded From UniProt

complete

DANRE:TIM50

involved_in

GO:0006915: apoptotic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:TIM50

acts_upstream_of_or_within

GO:0001836: release of cytochrome c from mitochondria

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:Q3ZCQ8

P

Seeded From UniProt

complete

MOUSE:TIM50

enables

GO:0004721: phosphoprotein phosphatase activity

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:Q3ZCQ8

F

Seeded From UniProt

complete

MOUSE:TIM50

enables

GO:0005134: interleukin-2 receptor binding

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:Q3ZCQ8

F

Seeded From UniProt

complete

MOUSE:HTRA2

located_in

GO:0005758: mitochondrial intermembrane space

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:O43464

C

Seeded From UniProt

complete

MOUSE:TIM23

located_in

GO:0005758: mitochondrial intermembrane space

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:O14925

C

Seeded From UniProt

complete

MOUSE:HTRA2

part_of

GO:0005758: mitochondrial intermembrane space

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:O43464

C

Seeded From UniProt

complete

See also

References

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