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Mpf1 is a novel factor that affects the dual distribution of tail-anchored proteins between mitochondria and peroxisomes

ABSTRACT: Over half of cellular proteins must target upon their translation to distinct cellular compartments to function. Whereas considerable progress has been made in our understanding of targeting to individual organelles, we know truly little about how proteins distribute their targeting between two, or more, destinations – a process called dual/multiple targeting. In this study, we shine mechanistic insight into the process of dual targeting of proteins between the yeast mitochondria and peroxisomes. We performed a high throughput systematic microscopy screen in which we visualized the location of the model tail-anchored (TA) proteins Fis1 and Gem1 on the background of mutants in all yeast genes. This screen identified three proteins, whose absence resulted in a higher portion of the TA proteins in peroxisomes: the two paralogues Tom70, Tom71, as well as the uncharacterized gene YNL144C that we renamed mitochondria peroxisomes factor 1 (Mpf1). We characterized Mpf1 to be an unstable protein that associated with the cytosolic face of the mitochondrial outer membrane. Furthermore, our study uncovers a unique contribution of Tom71 for the regulation of the dual targeting and reveals a link between TOM70/71 and the quantity of transcripts of MPF1. Collectively, our study revealed, for the first-time, factors that influence the dual targeting of proteins between mitochondria and peroxisomes.

ORGANISM(S): Saccharomyces cerevisiae (brewer's yeast)

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PROVIDER: S-BSST1871 | biostudies-other |

REPOSITORIES: biostudies-other

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Mpf1 affects the dual distribution of tail-anchored proteins between mitochondria and peroxisomes

Project description:Most cellular proteins require targeting to a distinct cellular compartment to function properly. A subset of proteins is distributed to two or more destinations in the cell and little is known about the mechanisms controlling the process of dual/multiple targeting. Here, we provide insight into the mechanism of dual targeting of proteins between mitochondria and peroxisomes. We perform a high throughput microscopy screen in which we visualize the location of the model tail-anchored proteins Fis1 and Gem1 in the background of mutants in virtually all yeast genes. This screen identifies three proteins, whose absence results in a higher portion of the tail-anchored proteins in peroxisomes: the two paralogues Tom70, Tom71, and the uncharacterized gene YNL144C that we rename mitochondria and peroxisomes factor 1 (Mpf1). We characterize Mpf1 to be an unstable protein that associates with the cytosolic face of the mitochondrial outer membrane. Furthermore, our study uncovers a unique contribution of Tom71 to the regulation of dual targeting. Collectively, our study reveals, for the first time, factors that influence the dual targeting of proteins between mitochondria and peroxisomes.

| S-SCDT-10_1038-S44319-025-00440-6 | biostudies-other

The subset of peroxisomal tail-anchored proteins do not reach peroxisomes via ER, instead mitochondria can be involved.

Project description:Peroxisomes are membrane-enclosed organelles with important roles in fatty acid breakdown, bile acid synthesis and biosynthesis of sterols and ether lipids. Defects in peroxisomes result in severe genetic diseases, such as Zellweger syndrome and neonatal adrenoleukodystrophy. However, many aspects of peroxisomal biogenesis are not well understood. Here we investigated delivery of tail-anchored (TA) proteins to peroxisomes in mammalian cells. Using glycosylation assays we showed that peroxisomal TA proteins do not enter the endoplasmic reticulum (ER) in both wild type (WT) and peroxisome-lacking cells. We observed that in cells lacking the essential peroxisome biogenesis factor, PEX19, peroxisomal TA proteins localize mainly to mitochondria. Finally, to investigate peroxisomal TA protein targeting in cells with fully functional peroxisomes we used a proximity biotinylation approach. We showed that while ER-targeted TA construct was exclusively inserted into the ER, peroxisome-targeted TA construct was inserted to both peroxisomes and mitochondria. Thus, in contrast to previous studies, our data suggest that some peroxisomal TA proteins do not insert to the ER prior to their delivery to peroxisomes, instead, mitochondria can be involved.

| S-EPMC10691693 | biostudies-literature

GET pathway mediates transfer of mislocalized tail-anchored proteins from mitochondria to the ER.

Project description:Tail-anchored (TA) membrane proteins have a potential risk to be mistargeted to the mitochondrial outer membrane (OM). Such mislocalized TA proteins can be extracted by the mitochondrial AAA-ATPase Msp1 from the OM and transferred to the ER for ER protein quality control involving ubiquitination by the ER-resident Doa10 complex. Yet it remains unclear how the extracted TA proteins can move to the ER crossing the aqueous cytosol and whether this transfer to the ER is essential for the clearance of mislocalized TA proteins. Here we show by time-lapse microscopy that mislocalized TA proteins, including an authentic ER-TA protein, indeed move from mitochondria to the ER in a manner strictly dependent on Msp1 expression. The Msp1-dependent mitochondria-to-ER transfer of TA proteins is blocked by defects in the GET system, and this block is not due to impaired Doa10 functions. Thus, the GET pathway facilitates the transfer of mislocalized TA proteins from mitochondria to the ER.

| S-EPMC9026240 | biostudies-literature

Mitochondrial AAA-ATPase Msp1 detects mislocalized tail-anchored proteins through a dual-recognition mechanism.

Project description:The conserved AAA-ATPase Msp1 is embedded in the outer mitochondrial membrane and removes mislocalized tail-anchored (TA) proteins upon dysfunction of the guided entry of tail-anchored (GET) pathway. It remains unclear how Msp1 recognizes its substrates. Here, we extensively characterize Msp1 and its substrates, including the mitochondrially targeted Pex15Δ30, and full-length Pex15, which mislocalizes to mitochondria upon dysfunction of Pex19 but not the GET pathway. Moreover, we identify two new substrates, Frt1 and Ysy6. Our results suggest that mislocalized TA proteins expose hydrophobic surfaces in the cytoplasm and are recognized by Msp1 through conserved hydrophobic residues. Introducing a hydrophobic patch into mitochondrial TA proteins transforms them into Msp1 substrates. In addition, Pex15Δ30 and Frt1 contain basic inter-membrane space (IMS) residues critical for their mitochondrial mistargeting. Remarkably, Msp1 recognizes this feature through the acidic D12 residue in its IMS domain. This dual-recognition mechanism involving interactions at the cytoplasmic and IMS domains of Msp1 and substrates greatly facilitates substrate recognition and is required by Msp1 to safeguard mitochondrial functions.

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

Project description: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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Tail-anchored PEX26 targets peroxisomes via a PEX19-dependent and TRC40-independent class I pathway.

Project description:Tail-anchored (TA) proteins are anchored into cellular membranes by a single transmembrane domain (TMD) close to the C terminus. Although the targeting of TA proteins to peroxisomes is dependent on PEX19, the mechanistic details of PEX19-dependent targeting and the signal that directs TA proteins to peroxisomes have remained elusive, particularly in mammals. The present study shows that PEX19 formed a complex with the peroxisomal TA protein PEX26 in the cytosol and translocated it directly to peroxisomes by interacting with the peroxisomal membrane protein PEX3. Unlike in yeast, the adenosine triphosphatase TRC40, which delivers TA proteins to the endoplasmic reticulum, was dispensable for the peroxisomal targeting of PEX26. Moreover, the basic amino acids within the luminal domain of PEX26 were essential for binding to PEX19 and thereby for peroxisomal targeting. Finally, our results suggest that a TMD that escapes capture by TRC40 and is followed by a highly basic luminal domain directs TA proteins to peroxisomes via the PEX19-dependent route.

| S-EPMC3587837 | biostudies-literature

Identification of novel tail-anchored membrane proteins integrated by the bacterial twin-arginine translocase.

Project description:The twin-arginine protein transport (Tat) system exports folded proteins across the cytoplasmic membranes of prokaryotes and the energy transducing-membranes of plant thylakoids and mitochondria. Proteins are targeted to the Tat machinery by N-terminal signal peptides with a conserved twin-arginine motif, and some substrates are exported as heterodimers where the signal peptide is present on one of the partner proteins. A subset of Tat substrates is found in the membrane. Tat-dependent membrane proteins usually have large globular domains and a single transmembrane helix present at the N- or C-terminus. Five Tat substrates that have C-terminal transmembrane helices have previously been characterized in the model bacterium Escherichia coli. Each of these is an iron-sulfur cluster-containing protein involved in electron transfer from hydrogen or formate. Here we have undertaken a bioinformatic search to identify further tail-anchored Tat substrates encoded in bacterial genomes. Our analysis has revealed additional tail-anchored iron-sulfur proteins associated in modules with either a b-type cytochrome or a quinol oxidase. We also identified further candidate tail-anchored Tat substrates, particularly among members of the actinobacterial phylum, that are not predicted to contain cofactors. Using reporter assays, we show experimentally that six of these have both N-terminal Tat signal peptides and C-terminal transmembrane helices. The newly identified proteins include a carboxypeptidase and a predicted protease, and four sortase substrates for which membrane integration is a prerequisite for covalent attachment to the cell wall.

| S-EPMC10924467 | biostudies-literature

Conserved and novel functions for Arabidopsis thaliana MIA40 in assembly of proteins in mitochondria and peroxisomes.

Project description:The disulfide relay system of the mitochondrial intermembrane space has been extensively characterized in Saccharomyces cerevisiae. It contains two essential components, Mia40 and Erv1. The genome of Arabidopsis thaliana contains a single gene for each of these components. Although insertional inactivation of Erv1 leads to a lethal phenotype, inactivation of Mia40 results in no detectable deleterious phenotype. A. thaliana Mia40 is targeted to and accumulates in mitochondria and peroxisomes. Inactivation of Mia40 results in an alteration of several proteins in mitochondria, an absence of copper/zinc superoxide dismutase (CSD1), the chaperone for superoxide dismutase (Ccs1) that inserts copper into CSD1, and a decrease in capacity and amount of complex I. In peroxisomes the absence of Mia40 leads to an absence of CSD3 and a decrease in abnormal inflorescence meristem 1 (Aim1), a β-oxidation pathway enzyme. Inactivation of Mia40 leads to an alteration of the transcriptome of A. thaliana, with genes encoding peroxisomal proteins, redox functions, and biotic stress significantly changing in abundance. Thus, the mechanistic operation of the mitochondrial disulfide relay system is different in A. thaliana compared with other systems, and Mia40 has taken on new roles in peroxisomes and mitochondria.

| S-EPMC2975236 | biostudies-literature

Bat3 promotes the membrane integration of tail-anchored proteins.

Project description:The membrane integration of tail-anchored proteins at the endoplasmic reticulum (ER) is post-translational, with different tail-anchored proteins exploiting distinct cytosolic factors. For example, mammalian TRC40 has a well-defined role during delivery of tail-anchored proteins to the ER. Although its Saccharomyces cerevisiae equivalent, Get3, is known to function in concert with at least four other components, Get1, Get2, Get4 and Get5 (Mdy2), the role of additional mammalian proteins during tail-anchored protein biogenesis is unclear. To this end, we analysed the cytosolic binding partners of Sec61beta, a well-defined substrate of TRC40, and identified Bat3 as a previously unknown interacting partner. Depletion of Bat3 inhibits the membrane integration of Sec61beta, but not of a second, TRC40-independent, tail-anchored protein, cytochrome b5. Thus, Bat3 influences the in vitro membrane integration of tail-anchored proteins using the TRC40 pathway. When expressed in Saccharomyces cerevisiae lacking a functional GET pathway for tail-anchored protein biogenesis, Bat3 associates with the resulting cytosolic pool of non-targeted chains and diverts it to the nucleus. This Bat3-mediated mislocalisation is not dependent upon Sgt2, a recently identified component of the yeast GET pathway, and we propose that Bat3 either modulates the TRC40 pathway in higher eukaryotes or provides an alternative fate for newly synthesised tail-anchored proteins.

| S-EPMC2886740 | biostudies-literature

Development of a prediction system for tail-anchored proteins.

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| S-EPMC5025589 | biostudies-literature

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