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Reduced Protein Import via TIM23 SORT Drives Disease Pathology in TIMM50-Associated Mitochondrial Disease.
Crameri, Jordan J; Palmer, Catherine S; Stait, Tegan; Jackson, Thomas D; Lynch, Matthew; Sinclair, Adriane; Frajman, Leah E; Compton, Alison G; Coman, David; Thorburn, David R; Frazier, Ann E; Stojanovski, Diana.
Afiliación
  • Crameri JJ; Department of Biochemistry and Pharmacology, The University of Melbourne, Parkville, Victoria, Australia.
  • Palmer CS; The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia.
  • Stait T; Department of Biochemistry and Pharmacology, The University of Melbourne, Parkville, Victoria, Australia.
  • Jackson TD; The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia.
  • Lynch M; Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia.
  • Sinclair A; Victorian Clinical Genetics Services, Royal Children's Hospital, Parkville, Victoria, Australia.
  • Frajman LE; Department of Biochemistry and Pharmacology, The University of Melbourne, Parkville, Victoria, Australia.
  • Compton AG; The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia.
  • Coman D; Neurosciences Department, Queensland Children's Hospital, South Brisbane, Queensland, Australia.
  • Thorburn DR; Department of Metabolic Medicine, Queensland Children's Hospital, South Brisbane, Queensland, Australia.
  • Frazier AE; School of Medicine, University of Queensland, St Lucia, Queensland, Australia.
  • Stojanovski D; Neurosciences Department, Queensland Children's Hospital, South Brisbane, Queensland, Australia.
Mol Cell Biol ; 44(6): 226-244, 2024.
Article en En | MEDLINE | ID: mdl-38828998
ABSTRACT
TIMM50 is a core subunit of the TIM23 complex, the mitochondrial inner membrane translocase responsible for the import of pre-sequence-containing precursors into the mitochondrial matrix and inner membrane. Here we describe a mitochondrial disease patient who is homozygous for a novel variant in TIMM50 and establish the first proteomic map of mitochondrial disease associated with TIMM50 dysfunction. We demonstrate that TIMM50 pathogenic variants reduce the levels and activity of endogenous TIM23 complex, which significantly impacts the mitochondrial proteome, resulting in a combined oxidative phosphorylation (OXPHOS) defect and changes to mitochondrial ultrastructure. Using proteomic data sets from TIMM50 patient fibroblasts and a TIMM50 HEK293 cell model of disease, we reveal that laterally released substrates imported via the TIM23SORT complex pathway are most sensitive to loss of TIMM50. Proteins involved in OXPHOS and mitochondrial ultrastructure are enriched in the TIM23SORT substrate pool, providing a biochemical mechanism for the specific defects in TIMM50-associated mitochondrial disease patients. These results highlight the power of using proteomics to elucidate molecular mechanisms of disease and uncovering novel features of fundamental biology, with the implication that human TIMM50 may have a more pronounced role in lateral insertion than previously understood.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fosforilación Oxidativa / Transporte de Proteínas / Enfermedades Mitocondriales / Proteínas del Complejo de Importación de Proteínas Precursoras Mitocondriales / Mitocondrias Límite: Humans Idioma: En Revista: Mol Cell Biol Año: 2024 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fosforilación Oxidativa / Transporte de Proteínas / Enfermedades Mitocondriales / Proteínas del Complejo de Importación de Proteínas Precursoras Mitocondriales / Mitocondrias Límite: Humans Idioma: En Revista: Mol Cell Biol Año: 2024 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Estados Unidos