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OM14 is a mitochondrial receptor for cytosolic ribosomes that supports co-translational import into mitochondria.

ABSTRACT: It is well established that import of proteins into mitochondria can occur after their complete synthesis by cytosolic ribosomes. Recently, an additional model was revived, proposing that some proteins are imported co-translationally. This model entails association of ribosomes with the mitochondrial outer membrane, shown to be mediated through the ribosome-associated chaperone nascent chain-associated complex (NAC). However, the mitochondrial receptor of this complex is unknown. Here, we identify the Saccharomyces cerevisiae outer membrane protein OM14 as a receptor for NAC. OM14? mitochondria have significantly lower amounts of associated NAC and ribosomes, and ribosomes from NAC[?] cells have reduced levels of associated OM14. Importantly, mitochondrial import assays reveal a significant decrease in import efficiency into OM14? mitochondria, and OM14-dependent import necessitates NAC. Our results identify OM14 as the first mitochondrial receptor for ribosome-associated NAC and reveal its importance for import. These results provide a strong support for an additional, co-translational mode of import into mitochondria.

SUBMITTER: Lesnik C

PROVIDER: S-EPMC4268710 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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OM14 is a mitochondrial receptor for cytosolic ribosomes that supports co-translational import into mitochondria.

Lesnik Chen C Cohen Yifat Y Atir-Lande Avigail A Schuldiner Maya M Arava Yoav Y

Nature communications 20141209

It is well established that import of proteins into mitochondria can occur after their complete synthesis by cytosolic ribosomes. Recently, an additional model was revived, proposing that some proteins are imported co-translationally. This model entails association of ribosomes with the mitochondrial outer membrane, shown to be mediated through the ribosome-associated chaperone nascent chain-associated complex (NAC). However, the mitochondrial receptor of this complex is unknown. Here, we identi ...[more]

PMID: 25487825

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Project description:Neurodegeneration is characterized by protein aggregate deposits and mitochondrial malfunction. Reduction in Tom40 (translocase of outer membrane 40) expression, a key subunit of the translocase of the outer mitochondrial membrane complex, led to accumulation of ubiquitin (Ub)-positive protein aggregates engulfed by Atg8a-positive membranes. Other macroautophagy markers were also abnormally accumulated. Autophagy was induced but the majority of autophagosomes failed to fuse with lysosomes when Tom40 was downregulated. In Tom40 RNAi tissues, autophagosome-like (AL) structures, often not sealed, were 10 times larger than starvation induced autophagosomes. Atg5 downregulation abolished Tom40 RNAi induced AL structure formation, but the Ub-positive aggregates remained, whereas knock down of Syx17, a gene required for autophagosome-lysosome fusion, led to the disappearance of giant AL structures and accumulation of small autophagosomes and phagophores near the Ub-positive aggregates. The protein aggregates contained many mitochondrial preproteins, cytosolic proteins, and proteasome subunits. Proteasome activity and ATP levels were reduced and the ROS levels was increased in Tom40 RNAi tissues. The simultaneous inhibition of proteasome activity, reduction in ATP production, and increase in ROS, but none of these conditions alone, can mimic the imbalanced proteostasis phenotypes observed in Tom40 RNAi cells. Knockdown of ref(2)P or ectopic expression of Pink1 and park greatly reduced aggregate formation in Tom40 RNAi tissues. In nerve tissues, reduction in Tom40 activity leads to aggregate formation and neurodegeneration. Rather than diminishing the neurodegenerative phenotypes, overexpression of Pink1 enhanced them. We proposed that defects in mitochondrial protein import may be the key to linking imbalanced proteostasis and mitochondrial defects.AbbreviationsAL: autophagosome-like; Atg12: Autophagy-related 12; Atg14: Autophagy-related 14; Atg16: Autophagy-related 16; Atg5: Autophagy-related 5; Atg6: Autophagy-related 6; Atg8a: Autophagy-related 8a; Atg9: Autophagy-related 9; ATP: adenosine triphosphate; Cas9: CRISPR associated protein 9; cDNA: complementary DNA; COX4: Cytochrome c oxidase subunit 4; CRISPR: clustered regularly interspaced short palindromic repeats; Cyt-c1: Cytochrome c1; DAPI: 4,6-diamidino-2-phenylindole dihydrochloride; Dcr-2: Dicer-2; FLP: Flippase recombination enzyme; FRT: FLP recombination target; GFP: green fluorescent protein; GO: gene ontology; gRNA: guide RNA; Hsp60: Heat shock protein 60A; HDAC6: Histone deacetylase 6; htt: huntingtin; Idh: Isocitrate dehydrogenase; IFA: immunofluorescence assay; Irp-1A: Iron regulatory protein 1A; kdn: knockdown; Marf: Mitochondrial assembly regulatory factor; MitoGFP: Mitochondrial-GFP; MS: mass spectrometry; MTPAP: mitochondrial poly(A) polymerase; Nmnat: Nicotinamide mononucleotide adenylyltransferase; OE: overexpression; Pink1/PINK1: PTEN-induced putative kinase 1; polyQ: polyglutamine; PRKN: parkin RBR E3 ubiquitin protein ligase; Pros?4: proteasome ?4 subunit; Pros?1: proteasome ?1 subunit; Pros?5: proteasome ?5 subunit; Pros?7: proteasome ?7 subunit; ref(2)P: refractory to sigma P; RFP: red fluorescent protein; RNAi: RNA interference; ROS: reactive oxygen species; Rpn11: Regulatory particle non-ATPase 11; Rpt2: Regulatory particle triple-A ATPase 2; scu: scully; sicily: severe impairment of CI with lengthened youth; sesB: stress-sensitive B; Syx17: Syntaxin17; TEM: transmission electron microscopy; ttm50: tiny tim 50; Tom: translocase of the outer membrane; Tom20: translocase of outer membrane 20; Tom40: translocase of outer membrane 40; Tom70: translocase of outer membrane 70; UAS: upstream active sequence; Ub: ubiquitin; VNC: ventral nerve cord; ZFYVE1: zinc finger FYVE-type containing 1.

Dataset Information

OM14 is a mitochondrial receptor for cytosolic ribosomes that supports co-translational import into mitochondria.

Publications

OM14 is a mitochondrial receptor for cytosolic ribosomes that supports co-translational import into mitochondria.

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