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

INSTRUMENT(S): Q Exactive

ORGANISM(S): Trypanosoma Brucei

SUBMITTER: Julian Bender

LAB HEAD: Bettina Warscheid

PROVIDER: PXD039631 | Pride | 2023-07-26

REPOSITORIES: Pride

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

2023-07-26 | PXD039634 | Pride

Receptor-mediated recruitment of cytosolic J-proteins to the mitochondrial outer membrane promotes assembly of preprotein translocases

Project description:Mitochondria possess elaborate machineries for the import of preproteins from the cytosol. Cytosolic factors like Hsp70 chaperones and their co-chaperones, the J-proteins, guide preproteins to the mitochondrial surface. The translocase of the mitochondrial outer membrane (TOM) forms the entry gate for precursor proteins. How proteins are delivered to the receptors Tom20, Tom22 and Tom70 is only understood in part. We identified the cytosolic J-protein Xdj1 as a specific interaction partner of the central receptor Tom22. Tom22 recruits Xdj1 to the mitochondrial surface to promote assembly of the TOM complex. A second J-protein of the cytosol, Djp1, binds to Tom70 to mediate biogenesis of the mitochondrial import (MIM) complex. Thus, by targeting distinct TOM receptors, cytosolic J-proteins promote the biogenesis of different mitochondrial preprotein translocases.

2018-11-26 | PXD008203 | Pride

Tom20 gates PINK1 activity and mediates its tethering of the TOM and TIM23 translocases upon mitochondrial stress

Project description:Mutations in PTEN-induced putative kinase 1 (PINK1) cause autosomal recessive early onset Parkinson disease (PD). PINK1 is a Ser/Thr kinase that regulates mitochondrial quality control by triggering mitophagy mediated by the ubiquitin ligase Parkin. Upon mitochondrial damage, PINK1 accumulates on the outer mitochondrial membrane (OMM) forming a high molecular weight complex with the translocase of the outer membrane (TOM). PINK1 then phosphorylates ubiquitin, which enables recruitment and activation of Parkin followed by autophagic clearance of the damaged mitochondrion. Thus, Parkin-dependent mitophagy hinges on the stable accumulation of PINK1 on the TOM complex. Yet, the mechanism linking mitochondrial stressors to PINK1 accumulation and whether the translocases of the inner membrane (TIMs) are also involved, remain unclear. Herein, we demonstrate that mitochondrial stress induces the formation of a PINK1-TOM-TIM23 supercomplex in human cultured cell lines, dopamine neurons, and midbrain organoids. Moreover, we show that PINK1 is required to stably tether the TOM to TIM23 complexes in response to stress, such that the supercomplex fails to accumulate in cells lacking PINK1. This tethering is dependent on an interaction between the PINK1 NT-CTE module and the cytosolic domain of the Tom20 subunit of the TOM complex, the disruption of which, by either designer or PD-associated PINK1 mutations, inhibits downstream mitophagy. Together, the findings provide key insight into how PINK1 interfaces with the mitochondrial import machinery, with important implications for the mechanisms of mitochondrial quality control and PD pathogenesis.

2024-03-02 | PXD047765 | Pride

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.

2018-04-20 | GSE107784 | GEO

The biochemical basis of mitochondrial dysfunction in Zellweger Spectrum Disorder

Project description:We identified that peroxins were still expressed in Zellweger Spectrum Disorder (ZSD) and a subset of them accumulated on the mitochondrial membrane, which resulted in gross mitochondrial abnormalities and impaired mitochondrial metabolic function. In this complexome analysis we detected several peroxins in the mitochondrial fraction in the absence of functional peroxisomes and that this accumulation is exacerbated by the loss of the mitochondrial extractase Msp1. In addition, we observed that specific peroxisomal matrix proteins localize to the mitochondria, which suggest that a functional peroxisomal docking and import complex assembles on the mitochondria in the absence of peroxisomes.

2021-06-25 | PXD024625 | Pride

TraB is a component of the ER-Mitochondrial contact site regulating ER-Mitochondrial interaction and mitophagy

Project description:ER-mitochondria contact sites (EMCSs) are important for mitochondrial function. Here, we have identified a EMCS complex, comprising a family of uncharacterised mitochondrial outer- membrane proteins, TraB1, TraB2 and the ER protein, VAP27-1. In Arabidopsis, there are three TraB isoforms and the trab1a/trab2 double mutant exhibits abnormal mitochondrial morphology, strong starch accumulation and impaired energy metabolism, indicating that these proteins are essential for normal mitochondrial function. Moreover, TraB1 and TraB2 proteins also interact with ATG8 in order to regulate mitochondrial degradation (mitophagy). The turnover of depolarised mitochondria is significantly reduced in both trab1/trab2 and VAP27 mutants (vap27-1,3,4,6) under mitochondrial stress conditions, with an increased population of dysfunctional mitochondria present in the cytoplasm. Consequently, plant recovery after stress is significantly perturbed, suggesting that TraB1 regulated mitophagy and ER-mitochondrial interaction are two closely related processes. Taken together, we ascribe a dual role to TraB1 which is a component of the EMCS complex in eukaryotes, regulating both interaction of the mitochondria to the ER and mitophagy.

2022-08-30 | PXD036285 | Pride

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]

2019-03-16 | GSE96726 | GEO

A MYC-driven change in mitochondrial dynamics limits stem cell properties of mammary epithelial cells (ChIP-seq)

Project description:In several developmental lineages, an increase in expression of the MYC proto-oncogene drives the transition from quiescent stem cells to transit amplifying cells. The mechanism by which MYC restricts self-renewal of adult stem cells is unknown. Here, we show that MYC activates a stereotypic transcriptional program of genes involved in protein translation and mitochondrial biogenesis in mammary epithelial cells and indirectly inhibits the YAP/TAZ co-activators that are essential for mammary stem cell self-renewal. We identify a phospholipase of the mitochondrial outer membrane, PLD6, as the mediator of MYC activity. PLD6 mediates a change in the mitochondrial fusion/fission balance that promotes nuclear export of YAP/TAZ in a LATS- and RHO-independent manner. Mouse models and human pathological data confirm that MYC suppresses YAP/TAZ activity in mammary tumors. PLD6 is also required for glutaminolysis, arguing that MYC-dependent changes in mitochondrial dynamics balance cellular energy metabolism with the self-renewal potential of adult stem cells. ChIP-Seq experiments for MYC-HA (HA-IP) performed in IMEC primary breast epithelial cells. Input-samples were sequenced as controlls.

2015-10-28 | E-GEOD-66252 | biostudies-arrayexpress

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

Project description:The ATPase Family AAA Domain Containing 3A (ATAD3A) is a mitochondrial inner membrane protein conserved in metazoans. ATAD3A has been associated with several mitochondrial functions, including nucleoid organization, cholesterol metabolism, and mitochondrial translation. To address its primary role, we generated a neuronal-specific conditional knockout (Atad3 nKO) mouse model, which developed a severe encephalopathy by 5 months of age. Pre-symptomatic mice showed aberrant mitochondrial cristae morphogenesis in the cortex as early as 2 months. Using a multi-omics approach in the CNS of 2-3-month-old mice, we found early alterations in the organelle membrane structure. We also showed that human ATAD3A associates with different components of the inner membrane, including: OXPHOS complex I, Letm1 and prohibitin complexes. Stochastic Optical Reconstruction Microscopy (STORM) showed that ATAD3A is regularly distributed along the inner mitochondrial membrane, suggesting a critical structural role in inner mitochondrial membrane and its organization, most likely in an ATPase-dependent manner.

2021-12-30 | GSE186409 | GEO

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