title: Unraveling the intricate organization of mammalian mitochondrial presequence translocases: existence of multiple translocases for maintenance of mitochondrial function.
abstract: Mitochondria are indispensable organelles implicated in multiple aspects of cellular processes, including tumorigenesis. Heat shock proteins play a critical regulatory role in accurately delivering the nucleus-encoded proteins through membrane-bound presequence translocase (Tim23 complex) machinery. Although altered expression of mammalian presequence translocase components had been previously associated with malignant phenotypes, the overall organization of Tim23 complexes is still unsolved. In this report, we show the existence of three distinct Tim23 complexes, namely, B1, B2, and A, involved in the maintenance of normal mitochondrial function. Our data highlight the importance of Magmas as a regulator of translocase function and in dynamically recruiting the J-proteins DnaJC19 and DnaJC15 to individual translocases. The basic housekeeping function involves translocases B1 and B2 composed of Tim17b isoforms along with DnaJC19, whereas translocase A is nonessential and has a central role in oncogenesis. Translocase B, having a normal import rate, is essential for constitutive mitochondrial functions such as maintenance of electron transport chain complex activity, organellar morphology, iron-sulfur cluster protein biogenesis, and mitochondrial DNA. In contrast, translocase A, though dispensable for housekeeping functions with a comparatively lower import rate, plays a specific role in translocating oncoproteins lacking presequence, leading to reprogrammed mitochondrial functions and hence establishing a possible link between the TIM23 complex and tumorigenicity.
authors.affiliation: Department of Biochemistry, Indian Institute of Science, Bangalore, India.
authors.forename: Devanjan
authors.initials: D
authors.lastname: Sinha
authors.forename: Shubhi
authors.initials: S
authors.lastname: Srivastava
authors.forename: Lekshmi
authors.initials: L
authors.lastname: Krishna
authors.forename: Patrick
authors.initials: P
authors.lastname: D'Silva
mesh_terms: D049109:Cell Proliferation; D056915:DNA Copy Number Variations; D004272:DNA, Mitochondrial / Q000235:genetics; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D008928:Mitochondria / Q000201:enzymology* / Q000235:genetics; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000201:enzymology*; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D024101:Mitochondrial Proteins / Q000378:metabolism; D021122:Protein Subunits / Q000378:metabolism; D021381:Protein Transport
chemical_list: D004272:DNA, Mitochondrial; D033681:Mitochondrial Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D024101:Mitochondrial Proteins; C503439:PAM16 protein, human; D021122:Protein Subunits; C534731:TIMM17A protein, human; C438387:TIMM23 protein, human