The Experts below are selected from a list of 177 Experts worldwide ranked by ideXlab platform
Morgan Sheng - One of the best experts on this subject based on the ideXlab platform.
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bax bak dependent release of ddp TIMM8A promotes drp1 mediated mitochondrial fission and mitoptosis during programmed cell death
Current Biology, 2005Co-Authors: Damien Arnoult, Neggy Rismanchi, Alain Grodet, Roland G Roberts, Daniel P Seeburg, Jerome Estaquier, Morgan Sheng, Craig BlackstoneAbstract:Summary Mitochondrial morphology within cells is controlled by precisely regulated rates of fusion and fission [1–4]. During programmed cell death (PCD), mitochondria undergo extensive fragmentation [5–7] and ultimately caspase-independent elimination through a process known as mitoptosis [8]. Though this increased fragmentation is due to increased fission through the recruitment of the dynamin-like GTPase Drp1 to mitochondria [9, 10], as well as to a block in mitochondrial fusion [11, 12], cellular mechanisms underlying these processes remain unclear. Here, we describe a mechanism for the increased mitochondrial Drp1 levels and subsequent stimulation of mitochondrial fission seen during PCD. We observed Bax/Bak-mediated release of DDP/TIMM8A, a mitochondrial intermembrane space (IMS) protein [13, 14], into the cytoplasm, where it binds to and promotes the mitochondrial redistribution of Drp1, a mediator of mitochondrial fission. Using both loss- and gain-of-function assays, we also demonstrate that the Drp1- and DDP/TIMM8A-dependent mitochondrial fragmentation observed during PCD is an important step in mitoptosis, which in turn is involved in caspase-independent cell death. Thus, following Bax/Bak-mediated mitochondrial outer membrane permeabilization (MOMP), IMS proteins released comprise not only apoptogenic factors such as cytochrome c involved in caspase activation [15, 16] but also DDP/TIMM8A, which activates Drp1-mediated fission to promote mitochondrial fragmentation and subsequently elimination during PCD.
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Bax/Bak-dependent release of DDP/TIMM8A promotes Drp1-mediated mitochondrial fission and mitoptosis during programmed cell death.
Current Biology, 2005Co-Authors: Damien Arnoult, Neggy Rismanchi, Alain Grodet, Roland G Roberts, Daniel P Seeburg, Jerome Estaquier, Morgan Sheng, Craig BlackstoneAbstract:Summary Mitochondrial morphology within cells is controlled by precisely regulated rates of fusion and fission [1–4]. During programmed cell death (PCD), mitochondria undergo extensive fragmentation [5–7] and ultimately caspase-independent elimination through a process known as mitoptosis [8]. Though this increased fragmentation is due to increased fission through the recruitment of the dynamin-like GTPase Drp1 to mitochondria [9, 10], as well as to a block in mitochondrial fusion [11, 12], cellular mechanisms underlying these processes remain unclear. Here, we describe a mechanism for the increased mitochondrial Drp1 levels and subsequent stimulation of mitochondrial fission seen during PCD. We observed Bax/Bak-mediated release of DDP/TIMM8A, a mitochondrial intermembrane space (IMS) protein [13, 14], into the cytoplasm, where it binds to and promotes the mitochondrial redistribution of Drp1, a mediator of mitochondrial fission. Using both loss- and gain-of-function assays, we also demonstrate that the Drp1- and DDP/TIMM8A-dependent mitochondrial fragmentation observed during PCD is an important step in mitoptosis, which in turn is involved in caspase-independent cell death. Thus, following Bax/Bak-mediated mitochondrial outer membrane permeabilization (MOMP), IMS proteins released comprise not only apoptogenic factors such as cytochrome c involved in caspase activation [15, 16] but also DDP/TIMM8A, which activates Drp1-mediated fission to promote mitochondrial fragmentation and subsequently elimination during PCD.
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interaction of the deafness dystonia protein ddp TIMM8A with the signal transduction adaptor molecule stam1
Biochemical and Biophysical Research Communications, 2003Co-Authors: Craig Blackstone, Roland G Roberts, Daniel P Seeburg, Morgan ShengAbstract:Abstract The Mohr–Tranebjaerg–Jensen deafness–dystonia–optic atrophy protein DDP/TIMM8A is translated on cytoplasmic ribosomes but targeted ultimately to the mitochondrial intermembrane space, where it is involved in mitochondrial protein import. STAM1 is a cytoplasmic signal-transducing adaptor molecule implicated in cytokine signaling. We report here a direct interaction between DDP and STAM1, identified by yeast two-hybrid screening and confirmed by co-immunoprecipitation, fusion protein “pull downs,” and nuclear redistribution assays. DDP coordinates Zn 2+ , and Zn 2+ was found to stimulate the DDP–STAM1 interaction in vitro. Endogenous STAM1 localizes predominantly to early endosomes, and we found no evidence that STAM1 is imported into mitochondria in vitro. Thus, the DDP–STAM1 interaction likely occurs in the cytoplasm or at the mitochondrial outer membrane. The DDP–STAM1 interaction requires a coiled-coil region in STAM1 that overlaps with the immunoreceptor tyrosine-based activation motif (ITAM), a region previously shown to be important for interaction with Jak2/3 and hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs). Thus, DDP binding may alter the interactions of STAM1 with several cytoplasmic proteins involved in cell signaling and endosomal trafficking.
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Interaction of the deafness-dystonia protein DDP/TIMM8A with the signal transduction adaptor molecule STAM1.
Biochemical and Biophysical Research Communications, 2003Co-Authors: Craig Blackstone, Roland G Roberts, Daniel P Seeburg, Morgan ShengAbstract:Abstract The Mohr–Tranebjaerg–Jensen deafness–dystonia–optic atrophy protein DDP/TIMM8A is translated on cytoplasmic ribosomes but targeted ultimately to the mitochondrial intermembrane space, where it is involved in mitochondrial protein import. STAM1 is a cytoplasmic signal-transducing adaptor molecule implicated in cytokine signaling. We report here a direct interaction between DDP and STAM1, identified by yeast two-hybrid screening and confirmed by co-immunoprecipitation, fusion protein “pull downs,” and nuclear redistribution assays. DDP coordinates Zn 2+ , and Zn 2+ was found to stimulate the DDP–STAM1 interaction in vitro. Endogenous STAM1 localizes predominantly to early endosomes, and we found no evidence that STAM1 is imported into mitochondria in vitro. Thus, the DDP–STAM1 interaction likely occurs in the cytoplasm or at the mitochondrial outer membrane. The DDP–STAM1 interaction requires a coiled-coil region in STAM1 that overlaps with the immunoreceptor tyrosine-based activation motif (ITAM), a region previously shown to be important for interaction with Jak2/3 and hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs). Thus, DDP binding may alter the interactions of STAM1 with several cytoplasmic proteins involved in cell signaling and endosomal trafficking.
Craig Blackstone - One of the best experts on this subject based on the ideXlab platform.
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bax bak dependent release of ddp TIMM8A promotes drp1 mediated mitochondrial fission and mitoptosis during programmed cell death
Current Biology, 2005Co-Authors: Damien Arnoult, Neggy Rismanchi, Alain Grodet, Roland G Roberts, Daniel P Seeburg, Jerome Estaquier, Morgan Sheng, Craig BlackstoneAbstract:Summary Mitochondrial morphology within cells is controlled by precisely regulated rates of fusion and fission [1–4]. During programmed cell death (PCD), mitochondria undergo extensive fragmentation [5–7] and ultimately caspase-independent elimination through a process known as mitoptosis [8]. Though this increased fragmentation is due to increased fission through the recruitment of the dynamin-like GTPase Drp1 to mitochondria [9, 10], as well as to a block in mitochondrial fusion [11, 12], cellular mechanisms underlying these processes remain unclear. Here, we describe a mechanism for the increased mitochondrial Drp1 levels and subsequent stimulation of mitochondrial fission seen during PCD. We observed Bax/Bak-mediated release of DDP/TIMM8A, a mitochondrial intermembrane space (IMS) protein [13, 14], into the cytoplasm, where it binds to and promotes the mitochondrial redistribution of Drp1, a mediator of mitochondrial fission. Using both loss- and gain-of-function assays, we also demonstrate that the Drp1- and DDP/TIMM8A-dependent mitochondrial fragmentation observed during PCD is an important step in mitoptosis, which in turn is involved in caspase-independent cell death. Thus, following Bax/Bak-mediated mitochondrial outer membrane permeabilization (MOMP), IMS proteins released comprise not only apoptogenic factors such as cytochrome c involved in caspase activation [15, 16] but also DDP/TIMM8A, which activates Drp1-mediated fission to promote mitochondrial fragmentation and subsequently elimination during PCD.
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Bax/Bak-dependent release of DDP/TIMM8A promotes Drp1-mediated mitochondrial fission and mitoptosis during programmed cell death.
Current Biology, 2005Co-Authors: Damien Arnoult, Neggy Rismanchi, Alain Grodet, Roland G Roberts, Daniel P Seeburg, Jerome Estaquier, Morgan Sheng, Craig BlackstoneAbstract:Summary Mitochondrial morphology within cells is controlled by precisely regulated rates of fusion and fission [1–4]. During programmed cell death (PCD), mitochondria undergo extensive fragmentation [5–7] and ultimately caspase-independent elimination through a process known as mitoptosis [8]. Though this increased fragmentation is due to increased fission through the recruitment of the dynamin-like GTPase Drp1 to mitochondria [9, 10], as well as to a block in mitochondrial fusion [11, 12], cellular mechanisms underlying these processes remain unclear. Here, we describe a mechanism for the increased mitochondrial Drp1 levels and subsequent stimulation of mitochondrial fission seen during PCD. We observed Bax/Bak-mediated release of DDP/TIMM8A, a mitochondrial intermembrane space (IMS) protein [13, 14], into the cytoplasm, where it binds to and promotes the mitochondrial redistribution of Drp1, a mediator of mitochondrial fission. Using both loss- and gain-of-function assays, we also demonstrate that the Drp1- and DDP/TIMM8A-dependent mitochondrial fragmentation observed during PCD is an important step in mitoptosis, which in turn is involved in caspase-independent cell death. Thus, following Bax/Bak-mediated mitochondrial outer membrane permeabilization (MOMP), IMS proteins released comprise not only apoptogenic factors such as cytochrome c involved in caspase activation [15, 16] but also DDP/TIMM8A, which activates Drp1-mediated fission to promote mitochondrial fragmentation and subsequently elimination during PCD.
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interaction of the deafness dystonia protein ddp TIMM8A with the signal transduction adaptor molecule stam1
Biochemical and Biophysical Research Communications, 2003Co-Authors: Craig Blackstone, Roland G Roberts, Daniel P Seeburg, Morgan ShengAbstract:Abstract The Mohr–Tranebjaerg–Jensen deafness–dystonia–optic atrophy protein DDP/TIMM8A is translated on cytoplasmic ribosomes but targeted ultimately to the mitochondrial intermembrane space, where it is involved in mitochondrial protein import. STAM1 is a cytoplasmic signal-transducing adaptor molecule implicated in cytokine signaling. We report here a direct interaction between DDP and STAM1, identified by yeast two-hybrid screening and confirmed by co-immunoprecipitation, fusion protein “pull downs,” and nuclear redistribution assays. DDP coordinates Zn 2+ , and Zn 2+ was found to stimulate the DDP–STAM1 interaction in vitro. Endogenous STAM1 localizes predominantly to early endosomes, and we found no evidence that STAM1 is imported into mitochondria in vitro. Thus, the DDP–STAM1 interaction likely occurs in the cytoplasm or at the mitochondrial outer membrane. The DDP–STAM1 interaction requires a coiled-coil region in STAM1 that overlaps with the immunoreceptor tyrosine-based activation motif (ITAM), a region previously shown to be important for interaction with Jak2/3 and hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs). Thus, DDP binding may alter the interactions of STAM1 with several cytoplasmic proteins involved in cell signaling and endosomal trafficking.
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Interaction of the deafness-dystonia protein DDP/TIMM8A with the signal transduction adaptor molecule STAM1.
Biochemical and Biophysical Research Communications, 2003Co-Authors: Craig Blackstone, Roland G Roberts, Daniel P Seeburg, Morgan ShengAbstract:Abstract The Mohr–Tranebjaerg–Jensen deafness–dystonia–optic atrophy protein DDP/TIMM8A is translated on cytoplasmic ribosomes but targeted ultimately to the mitochondrial intermembrane space, where it is involved in mitochondrial protein import. STAM1 is a cytoplasmic signal-transducing adaptor molecule implicated in cytokine signaling. We report here a direct interaction between DDP and STAM1, identified by yeast two-hybrid screening and confirmed by co-immunoprecipitation, fusion protein “pull downs,” and nuclear redistribution assays. DDP coordinates Zn 2+ , and Zn 2+ was found to stimulate the DDP–STAM1 interaction in vitro. Endogenous STAM1 localizes predominantly to early endosomes, and we found no evidence that STAM1 is imported into mitochondria in vitro. Thus, the DDP–STAM1 interaction likely occurs in the cytoplasm or at the mitochondrial outer membrane. The DDP–STAM1 interaction requires a coiled-coil region in STAM1 that overlaps with the immunoreceptor tyrosine-based activation motif (ITAM), a region previously shown to be important for interaction with Jak2/3 and hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs). Thus, DDP binding may alter the interactions of STAM1 with several cytoplasmic proteins involved in cell signaling and endosomal trafficking.
Lisbeth Tranebjaerg - One of the best experts on this subject based on the ideXlab platform.
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Mitochondrial Diseases Caused by Mutations in Inner Membrane Chaperone Proteins
Mitochondrial Disorders Caused by Nuclear Genes, 2012Co-Authors: Lisbeth TranebjaergAbstract:This chapter summarizes current knowledge of several disorders associated with the dysfunction of the mitochondrial membrane chaperone proteins, and pays particular attention to the X-linked recessive Mohr–Tranebjaerg syndrome (MTS), also called deafness-dystonia-optic neuronopathy syndrome (DDON syndrome), caused by mutations in TIMM8A.
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Alterations in expression levels of deafness dystonia protein 1 affect mitochondrial morphology
Human Molecular Genetics, 2011Co-Authors: Gertraud Engl, Lisbeth Tranebjaerg, Stefan Florian, Doron RapaportAbstract:Deafness-Dystonia-Optic Neuropathy (DDON) Syndrome is a rare X-linked progressive neurodegenerative disorder resulting from mutations in the TIMM8A gene encoding for the deafness dystonia protein 1 (DDP1). Despite important progress in identifying and characterizing novel mutations in this gene, little is known about the underlying pathomechanisms. Deficiencies in the biogenesis of hTim23 and consecutive alterations in biogenesis of inner membrane and matrix proteins have been proposed to serve as one possible mechanistic explanation. To shed new light on the role of DDP1 in the biogenesis of mammalian mitochondria, we investigated the effects of reduced or elevated DDP1 levels on mitochondrial dynamics and function. Our results show a reduction in the import of b-barrel proteins into mitochondria from cells overexpressing DDP1. This effect was not observed when the DDON-related mutant form DDP1-C66W was overexpressed. Live cell microscopy of primary fibroblasts derived from DDON patients and of DDP1 downregulated HeLa cells displayed alterations of mitochondrial morphology with notable extensions in the length of mitochondrial tubules, whereas overexpression of DDP1 induced the formation of hollow spherical mitochondria. Of note, knockdown of the TIMM8A gene by RNA interference did not show an influence on the oxygen respiration rate and the mitochondrial membrane potential. Taken together, these results suggest that alterations in the levels of DDP1 can affect the morphology of mitochondria and thus shed new light on the pathogenic mechanisms of DDON.
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Cochlear implantation in deafness-dystonia-optic neuronopathy (DDON) syndrome.
International Journal of Pediatric Otorhinolaryngology, 2007Co-Authors: James T. Brookes, Lisbeth Tranebjaerg, Adam B. Kanis, Abram P. Vore, Richard J.h. SmithAbstract:Summary To report the results of the first known cochlear implantation in a patient with deafness-dystonia-optic neuronopathy (DDON) syndrome (Mohr-Tranebaerg syndrome, DFN-1). DDON syndrome is an X-linked condition characterized by postlingual sensorineural hearing loss in early childhood followed by dystonia, psychosis, and optic atrophy in adolescence and adulthood. The gene responsible for the condition maps to Xq22 adjacent to the gene causally related to X-linked agammaglobulinemia. The audiometric characteristics of DDON syndrome are typical of auditory neuropathy, with spiral ganglion cells being the suspected site of pathology. Performance following cochlear implantation in auditory neuropathy patients is variable and has yet to be reported in any patients with DDON syndrome. The reported case describes a male initially diagnosed with X-linked agammaglobulinemia due to recurrent infections. Speech, language and hearing were typical of a child in the first year of life; however profound hearing loss developed and cochlear implantation was performed at age 4. Following implantation, further genetic workup determined that the patient carries a deletion that includes BTK and DDP1/TIMM8A , consistent with the diagnosis of X-linked agammaglobulinemia and DDON syndrome. The patient's performance with the cochlear implant was marginal even after 2 years of use, with continued poor scores in standardized speech, language and audiometric tests. Additionally, his most-comfortable-level implant setting requires higher-than-normal current applied to the electrode array. This case report supports other studies showing that DDON syndrome results in an auditory neuropathy. Further investigation is required to determine the efficacy of cochlear implantation in this patient population. DDON syndrome should be considered in patients with X-linked agammaglobulinemia and hearing loss.
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Otopathology in Mohr-Tranebjaerg syndrome.
Laryngoscope, 2007Co-Authors: Fayez Bahmad, Saumil N. Merchant, Joseph B. Nadol, Lisbeth TranebjaergAbstract:Background: Mohr-Tranebjaerg syndrome (MTS) is an X-linked, recessive, syndromic sensorineural hearing loss (HL) characterized by onset of deafness in childhood followed later in adult life by progressive neural degeneration affecting the brain and optic nerves. MTS is caused by mutations in the DDP/TIMM8A gene, which encodes for a 97 amino acid polypeptide; this polypeptide is a translocase of the inner mitochondrial membrane. Objectives: To describe the otologic presentation and temporal bone histopathology in four affected individuals with MTS. Material and Methods: All four subjects belonged to a large, multigenerational Norwegian family and were known to carry a frame shift mutation in the TIMM8A gene. Temporal bones were removed at autopsy and studied by light microscopy. Cytocochleograms were constructed for hair cells, stria vascularis, and cochlear neuronal cells. Vestibular neurons were also counted. Results: All four subjects developed progressive HL in early childhood, becoming profoundly deaf by the age of 10 years. All four developed language, and at least one subject used amplification in early life. Audiometric evaluation in two subjects showed 80- to 100-dB HL by the age of 10 years. The subjects died between the ages of 49 and 67. The otopathology was strikingly similar in that all bones examined showed near-total loss of cochlear neuronal cells and severe loss of vestibular neurons. When compared with age-matched controls, there was 90% to 95% loss of cochlear neurons and 75% to 85% loss of vestibular neurons. Conclusions: We infer that the HL in MTS is likely to be the result of a postnatal and progressive degeneration of cochlear neurons and that MTS constitutes a true auditory neuropathy. Our findings have implications for clinical diagnosis of patients with MTS and management of the HL.
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the calcium binding aspartate glutamate carriers citrin and aralar1 are new substrates for the ddp1 TIMM8A timm13 complex
Human Molecular Genetics, 2004Co-Authors: Karin Roesch, Lisbeth Tranebjaerg, Peter J Hynds, Renee Varga, Carla M KoehlerAbstract:The biogenesis of the mitochondrial inner membrane is dependent on two distinct 70 kDa protein complexes. TlMM8a partners with TIMM13 in the mitochondrial intermembrane space to form a 70 kDa complex and facilitates the import of the inner membrane substrate TIMM23. We have identified a new class of substrates, citrin and aralarl, which are Ca 2+ -binding aspartate/glutamate carriers (AGCs) of the mitochondrial inner membrane, using cross-linking and immunoprecipitation assays in isolated mitochondria. The AGCs function in the aspartate-malate NADH shuttle that moves reducing equivalents from the cytosol to the mitochondrial matrix. Mohr-Tranebjaerg syndrome (MTSIDFN-1, deafnessldystonia syndrome) results from a mutation in deafness/dystonia protein 1/translocase of mitochondrial inner membrane 8a (DDP1/TIMM8A) and loss of the 70 kDa complex. A lymphoblast cell line derived from an MTS patient had decreased NADH levels and defects in mitochondrial protein import. Protein expression studies indicate that DDP1 and TIMM13 show non-uniform expression in mammals, and expression is prominent in the large neurons in the brain, which is in agreement with the expression pattern of aralar1. Thus, insufficient NADH shuttling, linked with changes in Ca 2+ concentration, in sensitive cells of the central nervous system might contribute to the pathologic process associated with MTS.
Daniel P Seeburg - One of the best experts on this subject based on the ideXlab platform.
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bax bak dependent release of ddp TIMM8A promotes drp1 mediated mitochondrial fission and mitoptosis during programmed cell death
Current Biology, 2005Co-Authors: Damien Arnoult, Neggy Rismanchi, Alain Grodet, Roland G Roberts, Daniel P Seeburg, Jerome Estaquier, Morgan Sheng, Craig BlackstoneAbstract:Summary Mitochondrial morphology within cells is controlled by precisely regulated rates of fusion and fission [1–4]. During programmed cell death (PCD), mitochondria undergo extensive fragmentation [5–7] and ultimately caspase-independent elimination through a process known as mitoptosis [8]. Though this increased fragmentation is due to increased fission through the recruitment of the dynamin-like GTPase Drp1 to mitochondria [9, 10], as well as to a block in mitochondrial fusion [11, 12], cellular mechanisms underlying these processes remain unclear. Here, we describe a mechanism for the increased mitochondrial Drp1 levels and subsequent stimulation of mitochondrial fission seen during PCD. We observed Bax/Bak-mediated release of DDP/TIMM8A, a mitochondrial intermembrane space (IMS) protein [13, 14], into the cytoplasm, where it binds to and promotes the mitochondrial redistribution of Drp1, a mediator of mitochondrial fission. Using both loss- and gain-of-function assays, we also demonstrate that the Drp1- and DDP/TIMM8A-dependent mitochondrial fragmentation observed during PCD is an important step in mitoptosis, which in turn is involved in caspase-independent cell death. Thus, following Bax/Bak-mediated mitochondrial outer membrane permeabilization (MOMP), IMS proteins released comprise not only apoptogenic factors such as cytochrome c involved in caspase activation [15, 16] but also DDP/TIMM8A, which activates Drp1-mediated fission to promote mitochondrial fragmentation and subsequently elimination during PCD.
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Bax/Bak-dependent release of DDP/TIMM8A promotes Drp1-mediated mitochondrial fission and mitoptosis during programmed cell death.
Current Biology, 2005Co-Authors: Damien Arnoult, Neggy Rismanchi, Alain Grodet, Roland G Roberts, Daniel P Seeburg, Jerome Estaquier, Morgan Sheng, Craig BlackstoneAbstract:Summary Mitochondrial morphology within cells is controlled by precisely regulated rates of fusion and fission [1–4]. During programmed cell death (PCD), mitochondria undergo extensive fragmentation [5–7] and ultimately caspase-independent elimination through a process known as mitoptosis [8]. Though this increased fragmentation is due to increased fission through the recruitment of the dynamin-like GTPase Drp1 to mitochondria [9, 10], as well as to a block in mitochondrial fusion [11, 12], cellular mechanisms underlying these processes remain unclear. Here, we describe a mechanism for the increased mitochondrial Drp1 levels and subsequent stimulation of mitochondrial fission seen during PCD. We observed Bax/Bak-mediated release of DDP/TIMM8A, a mitochondrial intermembrane space (IMS) protein [13, 14], into the cytoplasm, where it binds to and promotes the mitochondrial redistribution of Drp1, a mediator of mitochondrial fission. Using both loss- and gain-of-function assays, we also demonstrate that the Drp1- and DDP/TIMM8A-dependent mitochondrial fragmentation observed during PCD is an important step in mitoptosis, which in turn is involved in caspase-independent cell death. Thus, following Bax/Bak-mediated mitochondrial outer membrane permeabilization (MOMP), IMS proteins released comprise not only apoptogenic factors such as cytochrome c involved in caspase activation [15, 16] but also DDP/TIMM8A, which activates Drp1-mediated fission to promote mitochondrial fragmentation and subsequently elimination during PCD.
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interaction of the deafness dystonia protein ddp TIMM8A with the signal transduction adaptor molecule stam1
Biochemical and Biophysical Research Communications, 2003Co-Authors: Craig Blackstone, Roland G Roberts, Daniel P Seeburg, Morgan ShengAbstract:Abstract The Mohr–Tranebjaerg–Jensen deafness–dystonia–optic atrophy protein DDP/TIMM8A is translated on cytoplasmic ribosomes but targeted ultimately to the mitochondrial intermembrane space, where it is involved in mitochondrial protein import. STAM1 is a cytoplasmic signal-transducing adaptor molecule implicated in cytokine signaling. We report here a direct interaction between DDP and STAM1, identified by yeast two-hybrid screening and confirmed by co-immunoprecipitation, fusion protein “pull downs,” and nuclear redistribution assays. DDP coordinates Zn 2+ , and Zn 2+ was found to stimulate the DDP–STAM1 interaction in vitro. Endogenous STAM1 localizes predominantly to early endosomes, and we found no evidence that STAM1 is imported into mitochondria in vitro. Thus, the DDP–STAM1 interaction likely occurs in the cytoplasm or at the mitochondrial outer membrane. The DDP–STAM1 interaction requires a coiled-coil region in STAM1 that overlaps with the immunoreceptor tyrosine-based activation motif (ITAM), a region previously shown to be important for interaction with Jak2/3 and hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs). Thus, DDP binding may alter the interactions of STAM1 with several cytoplasmic proteins involved in cell signaling and endosomal trafficking.
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Interaction of the deafness-dystonia protein DDP/TIMM8A with the signal transduction adaptor molecule STAM1.
Biochemical and Biophysical Research Communications, 2003Co-Authors: Craig Blackstone, Roland G Roberts, Daniel P Seeburg, Morgan ShengAbstract:Abstract The Mohr–Tranebjaerg–Jensen deafness–dystonia–optic atrophy protein DDP/TIMM8A is translated on cytoplasmic ribosomes but targeted ultimately to the mitochondrial intermembrane space, where it is involved in mitochondrial protein import. STAM1 is a cytoplasmic signal-transducing adaptor molecule implicated in cytokine signaling. We report here a direct interaction between DDP and STAM1, identified by yeast two-hybrid screening and confirmed by co-immunoprecipitation, fusion protein “pull downs,” and nuclear redistribution assays. DDP coordinates Zn 2+ , and Zn 2+ was found to stimulate the DDP–STAM1 interaction in vitro. Endogenous STAM1 localizes predominantly to early endosomes, and we found no evidence that STAM1 is imported into mitochondria in vitro. Thus, the DDP–STAM1 interaction likely occurs in the cytoplasm or at the mitochondrial outer membrane. The DDP–STAM1 interaction requires a coiled-coil region in STAM1 that overlaps with the immunoreceptor tyrosine-based activation motif (ITAM), a region previously shown to be important for interaction with Jak2/3 and hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs). Thus, DDP binding may alter the interactions of STAM1 with several cytoplasmic proteins involved in cell signaling and endosomal trafficking.
Roland G Roberts - One of the best experts on this subject based on the ideXlab platform.
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bax bak dependent release of ddp TIMM8A promotes drp1 mediated mitochondrial fission and mitoptosis during programmed cell death
Current Biology, 2005Co-Authors: Damien Arnoult, Neggy Rismanchi, Alain Grodet, Roland G Roberts, Daniel P Seeburg, Jerome Estaquier, Morgan Sheng, Craig BlackstoneAbstract:Summary Mitochondrial morphology within cells is controlled by precisely regulated rates of fusion and fission [1–4]. During programmed cell death (PCD), mitochondria undergo extensive fragmentation [5–7] and ultimately caspase-independent elimination through a process known as mitoptosis [8]. Though this increased fragmentation is due to increased fission through the recruitment of the dynamin-like GTPase Drp1 to mitochondria [9, 10], as well as to a block in mitochondrial fusion [11, 12], cellular mechanisms underlying these processes remain unclear. Here, we describe a mechanism for the increased mitochondrial Drp1 levels and subsequent stimulation of mitochondrial fission seen during PCD. We observed Bax/Bak-mediated release of DDP/TIMM8A, a mitochondrial intermembrane space (IMS) protein [13, 14], into the cytoplasm, where it binds to and promotes the mitochondrial redistribution of Drp1, a mediator of mitochondrial fission. Using both loss- and gain-of-function assays, we also demonstrate that the Drp1- and DDP/TIMM8A-dependent mitochondrial fragmentation observed during PCD is an important step in mitoptosis, which in turn is involved in caspase-independent cell death. Thus, following Bax/Bak-mediated mitochondrial outer membrane permeabilization (MOMP), IMS proteins released comprise not only apoptogenic factors such as cytochrome c involved in caspase activation [15, 16] but also DDP/TIMM8A, which activates Drp1-mediated fission to promote mitochondrial fragmentation and subsequently elimination during PCD.
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Bax/Bak-dependent release of DDP/TIMM8A promotes Drp1-mediated mitochondrial fission and mitoptosis during programmed cell death.
Current Biology, 2005Co-Authors: Damien Arnoult, Neggy Rismanchi, Alain Grodet, Roland G Roberts, Daniel P Seeburg, Jerome Estaquier, Morgan Sheng, Craig BlackstoneAbstract:Summary Mitochondrial morphology within cells is controlled by precisely regulated rates of fusion and fission [1–4]. During programmed cell death (PCD), mitochondria undergo extensive fragmentation [5–7] and ultimately caspase-independent elimination through a process known as mitoptosis [8]. Though this increased fragmentation is due to increased fission through the recruitment of the dynamin-like GTPase Drp1 to mitochondria [9, 10], as well as to a block in mitochondrial fusion [11, 12], cellular mechanisms underlying these processes remain unclear. Here, we describe a mechanism for the increased mitochondrial Drp1 levels and subsequent stimulation of mitochondrial fission seen during PCD. We observed Bax/Bak-mediated release of DDP/TIMM8A, a mitochondrial intermembrane space (IMS) protein [13, 14], into the cytoplasm, where it binds to and promotes the mitochondrial redistribution of Drp1, a mediator of mitochondrial fission. Using both loss- and gain-of-function assays, we also demonstrate that the Drp1- and DDP/TIMM8A-dependent mitochondrial fragmentation observed during PCD is an important step in mitoptosis, which in turn is involved in caspase-independent cell death. Thus, following Bax/Bak-mediated mitochondrial outer membrane permeabilization (MOMP), IMS proteins released comprise not only apoptogenic factors such as cytochrome c involved in caspase activation [15, 16] but also DDP/TIMM8A, which activates Drp1-mediated fission to promote mitochondrial fragmentation and subsequently elimination during PCD.
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interaction of the deafness dystonia protein ddp TIMM8A with the signal transduction adaptor molecule stam1
Biochemical and Biophysical Research Communications, 2003Co-Authors: Craig Blackstone, Roland G Roberts, Daniel P Seeburg, Morgan ShengAbstract:Abstract The Mohr–Tranebjaerg–Jensen deafness–dystonia–optic atrophy protein DDP/TIMM8A is translated on cytoplasmic ribosomes but targeted ultimately to the mitochondrial intermembrane space, where it is involved in mitochondrial protein import. STAM1 is a cytoplasmic signal-transducing adaptor molecule implicated in cytokine signaling. We report here a direct interaction between DDP and STAM1, identified by yeast two-hybrid screening and confirmed by co-immunoprecipitation, fusion protein “pull downs,” and nuclear redistribution assays. DDP coordinates Zn 2+ , and Zn 2+ was found to stimulate the DDP–STAM1 interaction in vitro. Endogenous STAM1 localizes predominantly to early endosomes, and we found no evidence that STAM1 is imported into mitochondria in vitro. Thus, the DDP–STAM1 interaction likely occurs in the cytoplasm or at the mitochondrial outer membrane. The DDP–STAM1 interaction requires a coiled-coil region in STAM1 that overlaps with the immunoreceptor tyrosine-based activation motif (ITAM), a region previously shown to be important for interaction with Jak2/3 and hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs). Thus, DDP binding may alter the interactions of STAM1 with several cytoplasmic proteins involved in cell signaling and endosomal trafficking.
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Interaction of the deafness-dystonia protein DDP/TIMM8A with the signal transduction adaptor molecule STAM1.
Biochemical and Biophysical Research Communications, 2003Co-Authors: Craig Blackstone, Roland G Roberts, Daniel P Seeburg, Morgan ShengAbstract:Abstract The Mohr–Tranebjaerg–Jensen deafness–dystonia–optic atrophy protein DDP/TIMM8A is translated on cytoplasmic ribosomes but targeted ultimately to the mitochondrial intermembrane space, where it is involved in mitochondrial protein import. STAM1 is a cytoplasmic signal-transducing adaptor molecule implicated in cytokine signaling. We report here a direct interaction between DDP and STAM1, identified by yeast two-hybrid screening and confirmed by co-immunoprecipitation, fusion protein “pull downs,” and nuclear redistribution assays. DDP coordinates Zn 2+ , and Zn 2+ was found to stimulate the DDP–STAM1 interaction in vitro. Endogenous STAM1 localizes predominantly to early endosomes, and we found no evidence that STAM1 is imported into mitochondria in vitro. Thus, the DDP–STAM1 interaction likely occurs in the cytoplasm or at the mitochondrial outer membrane. The DDP–STAM1 interaction requires a coiled-coil region in STAM1 that overlaps with the immunoreceptor tyrosine-based activation motif (ITAM), a region previously shown to be important for interaction with Jak2/3 and hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs). Thus, DDP binding may alter the interactions of STAM1 with several cytoplasmic proteins involved in cell signaling and endosomal trafficking.