MTCH2 is a mitochondrial outer membrane protein insertase

Guna, Alina; Stevens, Taylor; Inglis, Alison J.; Replogle, Joseph M.; Esantsi, Theodore K.; Muthukumar, Gayathri; Wang, Maxine L.; Pogson, Angela N; Jones, Jeff; Lomenick, Brett; Chou, Tsui‐Fen; Weissman, Jonathan S.; Voorhees, R.M.

doi:10.1101/2022.09.15.508165

Cited by 2 publications

(3 citation statements)

References 76 publications

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“…Intriguingly, there are hints that depletion of yeast MIM or mammalian MTCH2 may drive MAD pathways. Loss of these proteins does result in depletion in the level of at least some of their substrates (7,8), reminiscent of the proteasomal degradation of pATOM36 substrates by the MAD pathway described here.…”

Section: Discussionmentioning

confidence: 77%

“…The biogenesis of many α-helically membrane-anchored mitochondrial OM proteins is mediated by distinct protein factors in yeast (MIM complex), humans (MTCH2) and trypanosomes (pATOM36) (1)(2)(3)(4)(5)(6)8). Moreover, for the MIM complex and pATOM36, reciprocal complementation experiments demonstrate that they are functionally interchangeable (7).…”

Section: Resultsmentioning

confidence: 99%

“…Expression of pATOM36 in yeast lacking the MIM complex restores growth under non-permissive conditions, and vice versa, expression of the MIM complex complements the OM protein biogenesis defect in pATOM36-ablated trypanosomes (7). In human cells, the mitochondrial animal-specific carrier homolog 2 (MTCH2) is necessary and sufficient to insert α-helically anchored membrane proteins into the OM (8). However, at least in yeast, spontaneous insertion into the OM also seems possible for some proteins (9,10).…”

Section: Introductionmentioning

confidence: 99%

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A Msp1-containing complex removes orphaned proteins in the mitochondrial outer membrane of trypanosomes

Gerber

Suppanz

Oeljeklaus

et al. 2023

Preprint

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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 glycosomes and the mitochondrial outer membrane, where it forms a stable complex with four outer membrane proteins. The trypanosome-specific pATOM36 mediates complex assembly of a-helically anchored mitochondrial outer membrane proteins such as protein translocase subunits. Inhibition of their 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 not only Msp1 but also the trypanosomal homolog of the AAA-ATPase VCP are implicated in this quality control pathway. Moreover, in the absence of VCP three out of the four Msp1-interacting mitochondrial proteins are required for efficient proteasomal digestion of pATOM36 substrates suggesting they act in concert with Msp1. 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.

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Section: Discussionmentioning

confidence: 77%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Msp1-containing complex removes orphaned proteins in the mitochondrial outer membrane of trypanosomes

Gerber

Suppanz

Oeljeklaus

et al. 2023

Preprint

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The ER membrane protein complex governs lysosomal turnover of a mitochondrial tail-anchored protein, BNIP3, to restrict mitophagy

Delgado

Shepard

Lamson

et al. 2023

Preprint

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Lysosomal degradation of autophagy receptors is a common proxy for selective autophagy. However, we find that two established mitophagy receptors, BNIP3 and BNIP3L/NIX, violate this assumption. Rather, BNIP3 and NIX are constitutively delivered to lysosomes in an autophagy-independent manner. This alternative lysosomal delivery of BNIP3 accounts for nearly all of its lysosome-mediated degradation, even upon mitophagy induction. To identify how BNIP3, a tail-anchored protein in the outer mitochondrial membrane, is delivered to lysosomes, we performed a genome-wide CRISPR screen for factors influencing BNIP3 flux. By this approach, we revealed both known modifiers of BNIP3 stability as well as a pronounced reliance on endolysosomal components, including the ER membrane protein complex (EMC). Importantly, the endolysosomal system regulates BNIP3 alongside, but independent of, the ubiquitin-proteosome system (UPS). Perturbation of either mechanism is sufficient to modulate BNIP3-associated mitophagy and affect underlying cellular physiology. In short, while BNIP3 can be cleared by parallel and partially compensatory quality control pathways, non-autophagic lysosomal degradation of BNIP3 is a strong post-translational modifier of BNIP3 function. More broadly, these data reveal an unanticipated connection between mitophagy and TA protein quality control, wherein the endolysosomal system provides a critical axis for regulating cellular metabolism. Moreover, these findings extend recent models for tail-anchored protein quality control and install endosomal trafficking and lysosomal degradation in the canon of pathways that ensure tight regulation of endogenous TA protein localization.

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MTCH2 is a mitochondrial outer membrane protein insertase

Cited by 2 publications

References 76 publications

A Msp1-containing complex removes orphaned proteins in the mitochondrial outer membrane of trypanosomes

A Msp1-containing complex removes orphaned proteins in the mitochondrial outer membrane of trypanosomes

The ER membrane protein complex governs lysosomal turnover of a mitochondrial tail-anchored protein, BNIP3, to restrict mitophagy

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