Tim50, a component of the mitochondrial translocator, regulates mitochondrial integrity and cell death.
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.
Guo
Yin
Y
Center for Apoptosis Research and the Department of Microbiology and Immunology, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Cheong
NaEun
N
Zhang
ZhiJia
Z
De Rose
Robert
R
Deng
Yun
Y
Farber
Steven A
SA
Fernandes-Alnemri
Teresa
T
Alnemri
Emad S
ES
D000165:Acridine Orange / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins / Q000737:chemistry / Q000502:physiology*; D016923:Cell Death; D002460:Cell Line; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D015536:Down-Regulation; D005822:Genetic Vectors; D006801:Humans; D006863:Hydrogen-Ion Concentration; D015151:Immunoblotting; D017403:In Situ Hybridization; D008565:Membrane Proteins / Q000737:chemistry / Q000502:physiology*; D026901:Membrane Transport Proteins / Q000737:chemistry / Q000502:physiology*; D051379:Mice; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism; D009841:Oligonucleotides / Q000737:chemistry; D011233:Precipitin Tests; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000502:physiology*; D017386:Sequence Homology, Amino Acid; D019311:Staurosporine / Q000494:pharmacology; D013347:Subcellular Fractions; D013379:Substrate Specificity; D014018:Tissue Distribution; D014162:Transfection; D014357:Trypsin / Q000737:chemistry / Q000494:pharmacology; D020798:Two-Hybrid System Techniques; D014466:Ultraviolet Rays; D015027:Zebrafish
D002352:Carrier Proteins; D018076:DNA, Complementary; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D033681:Mitochondrial Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D009841:Oligonucleotides; D034741:RNA, Small Interfering; D029701:Saccharomyces cerevisiae Proteins; C083081:TIM23 protein, S cerevisiae; C469615:TIM50 protein, S cerevisiae; D045304:Cytochromes c; D014357:Trypsin; D000165:Acridine Orange; D019311:Staurosporine