The Mitochondrial Import Complex MIM Functions as Main Translocase for α-Helical Outer Membrane Proteins

Doan, Kim Nguyen; Grevel, Alexander; Mårtensson, Christoph U.; Ellenrieder, Lars; Thornton, Nicolas; Wenz, Lena‐Sophie; Opaliński, Łukasz; Guiard, Bernard; Pfanner, Nikolaus; Becker, Thomas

doi:10.1016/j.celrep.2020.107567

Cited by 71 publications

(65 citation statements)

References 66 publications

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“…Most studies on these proteins were carried out using the ADP/ATP carrier (AAC) as a model protein. However, other proteins have been described as additional Tom70 substrates, namely the β-barrel proteins of the mitochondrial outer membrane, single- and multi-membrane-spanning (polytopic) proteins and some non-canonical carriers [ 93 , 94 , 95 , 96 , 97 , 98 ]. Hence, the substrates of Tom70 are obviously diverse, but most of these proteins contain highly hydrophobic domains and thus have the tendency to aggregate outside their target membrane.…”

Section: Functions Of Tom70 In the Biogenesis Of Mitochondrial Promentioning

confidence: 99%

The Mitochondrial Outer Membrane Protein Tom70-Mediator in Protein Traffic, Membrane Contact Sites and Innate Immunity

Kreimendahl

Rassow

2020

IJMS

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Tom70 is a versatile adaptor protein of 70 kDa anchored in the outer membrane of mitochondria in metazoa, fungi and amoeba. The tertiary structure was resolved for the Tom70 of yeast, showing 26 α-helices, most of them participating in the formation of 11 tetratricopeptide repeat (TPR) motifs. Tom70 serves as a docking site for cytosolic chaperone proteins and co-chaperones and is thereby involved in the uptake of newly synthesized chaperone-bound proteins in mitochondrial biogenesis. In yeast, Tom70 additionally mediates ER-mitochondria contacts via binding to sterol transporter Lam6/Ltc1. In mammalian cells, TOM70 promotes endoplasmic reticulum (ER) to mitochondria Ca2+ transfer by association with the inositol-1,4,5-triphosphate receptor type 3 (IP3R3). TOM70 is specifically targeted by the Bcl-2-related protein MCL-1 that acts as an anti-apoptotic protein in macrophages infected by intracellular pathogens, but also in many cancer cells. By participating in the recruitment of PINK1 and the E3 ubiquitin ligase Parkin, TOM70 can be implicated in the development of Parkinson’s disease. TOM70 acts as receptor of the mitochondrial antiviral-signaling protein (MAVS) and thereby participates in the corresponding system of innate immunity against viral infections. The protein encoded by Orf9b in the genome of SARS-CoV-2 binds to TOM70, probably compromising the synthesis of type I interferons.

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Section: Functions Of Tom70 In the Biogenesis Of Mitochondrial Promentioning

confidence: 99%

The Mitochondrial Outer Membrane Protein Tom70-Mediator in Protein Traffic, Membrane Contact Sites and Innate Immunity

Kreimendahl

Rassow

2020

IJMS

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“…Therefore, in yeast cells, the targeting information of TA7 could be ambiguous and be recognized both as a mitochondrial and a peroxisomal signal. Similarly to Gem1 [15,17], TA7 is the only T. vaginalis protein requiring the MIM complex for its insertion. Since an orthologue of such a complex has not been identified yet in hydrogenosomes, most probably a complex without sequence similarity to the Mim proteins mediates the integration of TA7 to the hydrogenosomes membrane.…”

Section: Discussionmentioning

confidence: 99%

“…These results suggest that in yeast cells, HA-TA4 assumes in both ER and mitochondria a topology with the N-terminal soluble domain facing the lumen or the IMS, respectively. Recently, it has been observed that the MIM complex is required for the insertion of singlespan proteins, including the TA protein Gem1, into the MOM [15,17]. Therefore, we tested whether the deletion of Mim1, the central component of the MIM complex, affects the mitochondrial levels of HA-TA4.…”

Section: Plos Onementioning

confidence: 99%

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Hydrogenosomal tail-anchored proteins are targeted to both mitochondria and ER upon their expression in yeast cells

et al. 2020

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Some organisms, like Trichomonas vaginalis, contain mitochondria-related hydrogen-producing organelles, called hydrogenosomes. The protein targeting into these organelles is proposed to be similar to the well-studied mitochondria import. Indeed, S. cerevisiae mitochondria and T. vaginalis hydrogenosomes share some components of protein import complexes. However, it is still unknown whether targeting signals directing substrate proteins to hydrogenosomes can support in other eukaryotes specific mitochondrial localization. To address this issue, we investigated the intracellular localization of three hydrogenosomal tail-anchored proteins expressed in yeast cells. We observed that these proteins were targeted to both mitochondria and ER with a variable dependency on the mitochondrial MIM complex. Our results suggest that the targeting signal of TA proteins are only partially conserved between hydrogenosomes and yeast mitochondria.

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“…Many mitochondrial proteins, however, lack presequences and embark on other import routes into mitochondria. This is the case for all proteins of the outer membrane and most components of the intermembrane space (IMS) which employ several distinct pathways (Doan et al, 2020;Drwesh and Rapaport, 2020;Edwards et al, 2020;Finger and Riemer, 2020;Wiedemann and Pfanner, 2017). In addition, many mitochondrial inner membrane proteins, in particular the members of the metabolite carrier family (carriers for short) lack presequences and are imported via a distinct 'carrier pathway' (Horten et al, 2020;Rehling et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

The mitochondrial surface receptor Tom70 protects the cytosol against mitoprotein-induced stress

Backes

Bykov

Räschle

et al. 2020

Preprint

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SummaryMost mitochondrial proteins are synthesized as precursors in the cytosol and post-translationally transported into mitochondria. The mitochondrial surface protein Tom70 acts at the interface of the cytosol and mitochondria. In vitro import experiments identified Tom70 as targeting receptor, particularly for hydrophobic carriers. Using in vivo methods and high content screens, we revisited the question of Tom70 function and considerably expanded the set of Tom70-dependent mitochondrial proteins. We demonstrate that the crucial activity of Tom70 is its ability to recruit cytosolic chaperones to the outer membrane. Indeed, tethering an unrelated chaperone-binding domain onto the mitochondrial surface complements most of the defects caused by Tom70 deletion. Tom70-mediated chaperone recruitment reduces the proteotoxicity of mitochondrial precursor proteins, in particular of hydrophobic inner membrane proteins. Thus, our work suggests that the predominant function of Tom70 is to tether cytosolic chaperones to the outer mitochondrial membrane, rather than to serve as a mitochondria-specifying targeting receptor.

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The Mitochondrial Import Complex MIM Functions as Main Translocase for α-Helical Outer Membrane Proteins

Cited by 71 publications

References 66 publications

The Mitochondrial Outer Membrane Protein Tom70-Mediator in Protein Traffic, Membrane Contact Sites and Innate Immunity

The Mitochondrial Outer Membrane Protein Tom70-Mediator in Protein Traffic, Membrane Contact Sites and Innate Immunity

Hydrogenosomal tail-anchored proteins are targeted to both mitochondria and ER upon their expression in yeast cells

The mitochondrial surface receptor Tom70 protects the cytosol against mitoprotein-induced stress

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