“…Oxa1p interacts with the mitoribosome (Jia et al, 2003;Kohler et al, 2009) and is required for the co-translational membrane insertion of mitochondrial-encoded Atp6p, Atp9p, Cox1p, Cox2p, Cox3p and Cytb (Hell et al, 1997(Hell et al, , 1998(Hell et al, , 2001Jia et al, 2007). Oxa1p also appears to have a direct role in the insertion of nuclear-encoded inner mitochondrial membrane (IMM) proteins (Hell et al, 2001) including Oxa1p itself (Hell et al, 1998) and an indirect effect on many more IMM proteins including several metabolite transporters (Hildenbeutel et al, 2012), since Oxa1p is crucial for the biogenesis of the Tim18-Sdh3 module of the carrier translocase (Stiller et al, 2016).…”
OXA1, the mitochondrial member of the YidC/Alb3/Oxa1 membrane protein insertase family, is required for the assembly of oxidative phosphorylation complexes IV and V in yeast. However, depletion of human OXA1 (OXA1L) was previously reported to impair assembly of complexes I and V only. We report a patient presenting with severe encephalopathy, hypotonia and developmental delay who died at 5 years showing complex IV deficiency in skeletal muscle. Whole exome sequencing identified biallelic OXA1L variants (c.500_507dup, p.(Ser170Glnfs*18) and c.620G>T, p.(Cys207Phe)) that segregated with disease. Patient muscle and fibroblasts showed decreased OXA1L and subunits of complexes IV and V. Crucially, expression of wild‐type human OXA1L in patient fibroblasts rescued the complex IV and V defects. Targeted depletion of OXA1L in human cells or Drosophila melanogaster caused defects in the assembly of complexes I, IV and V, consistent with patient data. Immunoprecipitation of OXA1L revealed the enrichment of mtDNA‐encoded subunits of complexes I, IV and V. Our data verify the pathogenicity of these OXA1L variants and demonstrate that OXA1L is required for the assembly of multiple respiratory chain complexes.
“…Oxa1p interacts with the mitoribosome (Jia et al, 2003;Kohler et al, 2009) and is required for the co-translational membrane insertion of mitochondrial-encoded Atp6p, Atp9p, Cox1p, Cox2p, Cox3p and Cytb (Hell et al, 1997(Hell et al, , 1998(Hell et al, , 2001Jia et al, 2007). Oxa1p also appears to have a direct role in the insertion of nuclear-encoded inner mitochondrial membrane (IMM) proteins (Hell et al, 2001) including Oxa1p itself (Hell et al, 1998) and an indirect effect on many more IMM proteins including several metabolite transporters (Hildenbeutel et al, 2012), since Oxa1p is crucial for the biogenesis of the Tim18-Sdh3 module of the carrier translocase (Stiller et al, 2016).…”
OXA1, the mitochondrial member of the YidC/Alb3/Oxa1 membrane protein insertase family, is required for the assembly of oxidative phosphorylation complexes IV and V in yeast. However, depletion of human OXA1 (OXA1L) was previously reported to impair assembly of complexes I and V only. We report a patient presenting with severe encephalopathy, hypotonia and developmental delay who died at 5 years showing complex IV deficiency in skeletal muscle. Whole exome sequencing identified biallelic OXA1L variants (c.500_507dup, p.(Ser170Glnfs*18) and c.620G>T, p.(Cys207Phe)) that segregated with disease. Patient muscle and fibroblasts showed decreased OXA1L and subunits of complexes IV and V. Crucially, expression of wild‐type human OXA1L in patient fibroblasts rescued the complex IV and V defects. Targeted depletion of OXA1L in human cells or Drosophila melanogaster caused defects in the assembly of complexes I, IV and V, consistent with patient data. Immunoprecipitation of OXA1L revealed the enrichment of mtDNA‐encoded subunits of complexes I, IV and V. Our data verify the pathogenicity of these OXA1L variants and demonstrate that OXA1L is required for the assembly of multiple respiratory chain complexes.
“…However, plant mitochondria contain four members (OXA1a, OXA1b, OXA2a, and OXA2b), whose exact functions have not been investigated so far. Oxa1 plays a major role in the cotranslational insertion of mitochondrialencoded membrane proteins and also the posttranslational insertion of nuclear-encoded membrane proteins (Hildenbeutel et al, 2012;Thompson et al, 2018). In contrast to Oxa1, Cox18 has been demonstrated to have only one substrate protein, Cox2 (Saracco and Fox, 2002;Bourens and Barrientos, 2017).…”
The evolutionarily conserved YidC/Oxa1/Alb3 proteins are involved in the insertion of membrane proteins in all domains of life. In plant mitochondria, individual knockouts of OXA1a, OXA2a, and OXA2b are embryo-lethal. In contrast to other members of the protein family, OXA2a and OXA2b contain a tetratricopeptide repeat (TPR) domain at the C-terminus. Here, the role of Arabidopsis (Arabidopsis thaliana) OXA2b was determined by using viable mutant plants that were generated by complementing homozygous lethal OXA2b T-DNA insertional mutants with a C-terminally truncated OXA2b lacking the TPR domain. The truncated-OXA2b-complemented plants displayed severe growth retardation due to a strong reduction in the steady-state abundance and enzyme activity of the mitochondrial respiratory chain complex IV. The TPR domain of OXA2b directly interacts with cytochrome c oxidase subunit 2, aiding in efficient membrane insertion and translocation of its C-terminus. Thus, OXA2b is crucial for the biogenesis of complex IV in plant mitochondria.
“…Tim9, Tim10 and Tim12 also form a complex on the surface of the IM when they are associated with the TIM22 core [23], and Tim54 acts as an adaptor protein in this process by directly interacting with Tim10 [24,25]. Other proteins follow the Oxa1 (cytochrome oxidase activity 1) complex for their insertion into the IM (Figure 2) [26,27], which is a member of a large family of proteins that act to insert proteins into the membranes of mitochondria, chloroplasts and bacteria [6,28,29]. Figure 2.IM protein import pathway.IM precursors are imported into the IMS by the TOM complex, and then chaperoned across the IMS by small Tims to the TIM22 (translocase of the inner membrane 22) complex.…”
Section: Translocation Across the Mitochondrial Inner Membranementioning
Mitochondria fulfill a diverse range of functions in cells including oxygen metabolism, homeostasis of inorganic ions and execution of apoptosis. Biogenesis of mitochondria relies on protein import pathways that are ensured by dedicated multiprotein translocase complexes localized in all sub-compartments of these organelles. The key components and pathways involved in protein targeting and assembly have been characterized in great detail over the last three decades. This includes the oxidative folding machinery in the intermembrane space, which contributes to the redox-dependent control of proteostasis. Here, we focus on several components of this system and discuss recent evidence suggesting links to human proteopathy.
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