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An Msp1-containing complex removes orphaned proteins in the mitochondrial outer membrane of trypanosomes (RNAi knockdown data)

ABSTRACT: The AAA-ATPase Msp1 extracts mislocalized outer membrane proteins and thus contributes to mitochondrial proteostasis. Using pull down experiments, we show that trypanosomal Msp1 localizes to both the glycosome and the mitochondrial outer membrane, where it forms a stable complex with four outer membrane proteins. The trypanosome-specific pATOM36 mediates complex assembly of α-helically anchored mitochondrial outer membrane proteins, such as protein translocase subunits. Inhibition of complex assembly triggers a pathway that results in the proteasomal digestion of unassembled substrates. Using inducible single, double and triple RNAi cell lines combined with proteomic analyses, we demonstrate that both TbMsp1 and the trypanosomal homolog of a cytosolic AAA-ATPase, VCP, are implicated in this quality control pathway. Moreover, in the absence of TbVCP, three out of the four TbMsp1-interacting mitochondrial proteins are required for efficient proteasomal digestion of pATOM36 substrates, suggesting they act in concert with TbMsp1. pATOM36 is a functional analogue of the yeast MIM complex, and possibly of human MTCH2, suggesting that similar mitochondrial quality control pathways linked to Msp1 might also exist in yeast and humans.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Trypanosoma Brucei

SUBMITTER: Julian Bender

LAB HEAD: Bettina Warscheid

PROVIDER: PXD039634 | Pride | 2023-07-26

REPOSITORIES: Pride

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An Msp1-containing complex removes orphaned proteins in the mitochondrial outer membrane of trypanosomes (SILAC-IP data)

Project description:The AAA-ATPase Msp1 extracts mislocalized outer membrane proteins and thus contributes to mitochondrial proteostasis. Using pull down experiments, we show that trypanosomal Msp1 localizes to both the glycosome and the mitochondrial outer membrane, where it forms a stable complex with four outer membrane proteins. The trypanosome-specific pATOM36 mediates complex assembly of alpha-helically anchored mitochondrial outer membrane proteins, such as protein translocase subunits. Inhibition of complex assembly triggers a pathway that results in the proteasomal digestion of unassembled substrates. Using inducible single, double and triple RNAi cell lines combined with proteomic analyses, we demonstrate that both TbMsp1 and the trypanosomal homolog of a cytosolic AAA-ATPase, VCP, are implicated in this quality control pathway. Moreover, in the absence of TbVCP, three out of the four TbMsp1-interacting mitochondrial proteins are required for efficient proteasomal digestion of pATOM36 substrates, suggesting they act in concert with TbMsp1. pATOM36 is a functional analogue of the yeast MIM complex, and possibly of human MTCH2, suggesting that similar mitochondrial quality control pathways linked to Msp1 might also exist in yeast and humans.

2023-07-26 | PXD039631 | Pride

Release of a nuclear ubiquitin-like protein activates proteasomal degradation of mislocalized hydrophobic mitochondrial proteins in trypanosomes

Project description:Mitochondrial protein import in the parasitic protozoan Trypanosoma brucei is mediated by the atypical outer membrane translocase, ATOM. It consists of seven subunits including ATOM69, the import receptor for hydrophobic proteins. Ablation of ATOM69, but not of any other subunit, triggers a unique quality control pathway resulting in the proteasomal degradation of non-imported mitochondrial proteins. The process requires a protein of unknown function, an E3 ubiquitin ligase and the ubiquitin-like protein (TbUbL1), which all are recruited to the mitochondrion upon ATOM69 depletion. TbUbL1 is a nuclear protein, a fraction of which is released to the cytosol upon triggering of the pathway. Nuclear release is essential since cytosolic TbUbL1 can bind mislocalized mitochondrial proteins and likely transfers them to the proteasome. Mitochondrial quality control has previously been studied in yeast and metazoans. Finding such a pathway in the highly diverged trypanosomes suggests such pathways are an obligate feature of all mitochondria.

2022-05-04 | PXD027739 | Pride

Release of a nuclear ubiquitin-like protein activates proteasomal degradation of mislocalized hydrophobic mitochondrial proteins in trypanosomes

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Characterisation of a highly diverged putative mitochondrial ATP synthase peripheral stalk subunit b in Trypanosoma brucei

Project description:The mitochondrial F1Fo ATP synthase of Trypanosoma brucei has been studied in detail. Whereas its F1 moiety is relatively highly conserved in structure and composition, the same is not the case for the Fo part and the peripheral stalk. A core subunit of the latter, the normally conserved subunit b, could not be identified in trypanosomes suggesting that it might be absent. Here we have identified a 17 kDa mitochondrial protein of the inner membrane that is essential for normal growth, efficient oxidative phosphorylation and membrane potential maintenance. Pulldown experiments and native PAGE analysis indicate that the protein is associated with the F1Fo ATP synthase. Its knockdown reduces the levels of Fo subunits, but not those of F1, and disturbs the cell cycle. HHpred analysis showed that the protein has structural similarities to subunit b of other species, indicating that the Fo part of the trypanosomal ATP synthase does contain a highly diverged subunit b. Thus, the Fo part of the trypanosomal ATPase synthase may be more widely conserved than initially thought.

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mitoCPR - a surveillance pathway that protects mitochondria in response to mitochondrial import stress

Project description:Mitochondrial functions are essential for cell viability and rely on protein import into the organelle. Various disease and stress conditions can lead to mitochondrial import defects. We find that inhibition of mitochondrial import in budding yeast activates a surveillance mechanism, mitoCPR, that is aimed at ameliorating mitochondrial import and protecting mitochondria during import stress. mitoCPR induces expression of Cis1 which associates with the mitochondrial translocase to reduce the accumulation of mitochondrial precursor proteins at the organelle surface. Clearance of precursor proteins depends on the Cis1 interacting AAA+ ATPase Msp1 and the proteasome suggesting that Cis1 facilitates degradation of un-imported proteins at the mitochondrial surface.

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mitoCPR - a surveillance pathway that protects mitochondria in response to mitochondrial import stress [yeast]

Project description:Mitochondrial functions are essential for cell viability and rely on protein import into the organelle. Physiological perturbations and disease conditions can lead to mitochondrial import defect. We find that in budding yeast, mitochondrial import defects result in activation of a surveillance mechanism, which we termed mitoCPR. The mitoCPR is aimed at ameliorating mitochondrial import and protecting mitochondria during import stress. This is mediated by the mitoCPR effector, Cis1, which associates with mitochondria to reduce the accumulation of mitochondrial preproteins at the organelle's surface. Clearance of preproteins depends on the AAA-ATPase Msp1 and the proteasome, suggesting that Cis1 facilitates the degradation of unimported proteins that accumulate at the mitochondrial surface. We further show that mitoCPR is critical for maintaining mitochondrial functions during mitochondrial import stress and provide evidence that it is an ancient, conserved mitochondrial protection mechanism.

2019-03-16 | GSE96727 | GEO

mitoCPR - a surveillance pathway that protects mitochondria in response to mitochondrial import stress [human]

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STAT6 in mitochondrial outer membrane impairs mitochondrial fusion by inhibiting MFN2 dimerization

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LONP1 and mtHSP70 cooperate to promote mitochondrial protein folding

Project description:Because 99% of the mitochondrial proteome is encoded by the nucleus, most mitochondrial precursor polypeptides are imported from the cytosol into the mitochondrion, where they must efficiently fold into their functional state. Mitochondrial precursors are imported as unfolded polypeptides due to the limited pore size of the import machinery. For proteins of the mitochondrial matrix and inner membrane, two separate and highly conserved chaperone systems, HSP60 and mitochondrial HSP70 (mtHSP70), facilitate protein folding. Here we show that LONP1, a AAA+ protease of the mitochondrial matrix, works with the mtHSP70 chaperone system to promote mitochondrial protein folding. Inhibition of LONP1 results in aggregation of a protein subset similar to that caused by knockdown of DNAJA3, a co-chaperone of mtHSP70. LONP1 is required for DNAJA3 and mtHSP70 solubility, and its ATPase, but not its protease activity, is required for this function. In vitro, LONP1 collaborates with mtHSP70 and its co-factors to stabilize a folding intermediate of OXA1L. In the absence of LONP1, the interaction of mtHSP70 with OXA1L is futile and results in substrate-induced coaggregation. Our results identify mitochondrial LONP1 as a critical factor in the mtHSP70 folding pathway and directly demonstrate its long suspected chaperone activity.

2020-12-07 | PXD021939 | Pride

ATAD3A has a scaffolding role regulating mitochondria inner membrane structure and protein assembly

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