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The metabolite-controlled ubiquitin conjugase Ubc8 promotes mitochondrial protein import by enhancing assembly of the TOM complex - DATA SET II

ABSTRACT: Mitochondria are essential organelles that play a key role in energy metabolism. Transitions between glycolytic and respiring conditions induce considerable adaptations of the cellular proteome. These metabolism-dependent changes are particularly pronounced for the protein composition of mitochondria. Here we show that the ubiquitin conjugase Ubc8 of the yeast cytosol plays a crucial role in the remodeling process when cells are shifted from respiratory to fermentative conditions. Ubc8 is a conserved and well-studied component of the catabolite control system that is known to regulate the stability of gluconeogenesis enzymes. Unexpectedly, we found that Ubc8 also promotes the assembly of the translocase of the outer membrane of mitochondria (TOM) and stabilizes its cytosol-exposed receptor subunit Tom22. Ubc8 deficiency results in a compromised protein import into mitochondria and a subsequent accumulation of mitochondrial precursor proteins in the cytosol. Our observations show that Ubc8 which is controlled by the prevalent metabolic conditions, promotes on the one hand the switch from glucose synthesis to glucose usage in the cytosol and, on the other hand, the biogenesis of the mitochondrial TOM machinery in order to protect the mitochondrial import machinery during phases of metabolic transition.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Saccharomyces Cerevisiae (baker's Yeast)

TISSUE(S): Cell Culture

SUBMITTER: Markus Räschle

LAB HEAD: Markus Raeschle

PROVIDER: PXD036508 | Pride | 2022-10-15

REPOSITORIES: Pride

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The metabolite-controlled ubiquitin conjugase Ubc8 promotes mitochondrial protein import by enhancing assembly of the TOM complex

Project description:Mitochondria are essential organelles that play a key role in energy metabolism. Transitions between glycolytic and respiring conditions induce considerable adaptations of the cellular proteome. These metabolism-dependent changes are particularly pronounced for the protein composition of mitochondria. Here we show that the ubiquitin conjugase Ubc8 of the yeast cytosol plays a crucial role in the remodeling process when cells are shifted from respiratory to fermentative conditions. Ubc8 is a conserved and well-studied component of the catabolite control system that is known to regulate the stability of gluconeogenesis enzymes. Unexpectedly, we found that Ubc8 also promotes the assembly of the translocase of the outer membrane of mitochondria (TOM) and stabilizes its cytosol-exposed receptor subunit Tom22. Ubc8 deficiency results in a compromised protein import into mitochondria and a subsequent accumulation of mitochondrial precursor proteins in the cytosol. Our observations show that Ubc8 which is controlled by the prevalent metabolic conditions, promotes on the one hand the switch from glucose synthesis to glucose usage in the cytosol and, on the other hand, the biogenesis of the mitochondrial TOM machinery in order to protect the mitochondrial import machinery during phases of metabolic transition.

2022-10-15 | PXD033171 | Pride

The metabolite-controlled ubiquitin conjugase Ubc8 promotes mitochondrial protein import by enhancing assembly of the TOM complex - Data Set 2

2022-10-15 | PXD033193 | Pride

Mitochondrial protein import clogging as a mechanism of disease

Project description:Mitochondrial biogenesis requires the import of >1,000 mitochondrial preproteins from the cytosol. Most studies on mitochondrial protein import are focused on the core import machinery. Whether and how the biophysical properties of substrate preproteins affect overall import efficiency is underexplored. Here, we show that protein traffic into mitochondria can be disrupted by amino acid substitutions in a single substrate preprotein. Pathogenic missense mutations in adenine nucleotide translocase 1 (Ant1), and its yeast homolog Aac2, cause the protein to accumulate along the protein import pathway, thereby obstructing general protein translocation into mitochondria. This impairs mitochondrial respiration, cytosolic proteostasis and cell viability independent of Ant1’s nucleotide transport activity. The mutations act synergistically, as double mutant Aac2/Ant1 cause severe clogging primarily at the Translocase of the Outer Membrane (TOM) complex. This confers extreme toxicity in yeast. In mice, expression of a super-clogger Ant1 variant led to neurodegeneration and an age-dependent dominant myopathy that phenocopy Ant1-induced human disease, suggesting clogging as a mechanism of disease. More broadly, this work implies the existence of uncharacterized amino acid requirements for mitochondrial carrier proteins to avoid clogging and subsequent disease.

2023-03-17 | GSE227295 | GEO

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

Control of the mitochondrial carrier import pathway by DYRK1A

Project description:Mitochondria require a complete and functional proteome to maintain a plethora of metabolic reactions in a cell. Changes in cellular demands depend on a rapid adaptation of the mitochondrial proteome. The translocase of the outer membrane TOM, constitutes the organellar entry gate that imports nearly all proteins as precursors from the cytosol. It is therefore an ideal target for cytosolic signalling pathways to regulate organellar protein influx. Here we identify the human mitochondrial import receptor TOM70 as a target of the cytosolic kinase DYRK1A. Phosphorylation of TOM70Ser91 by DYRK1A does not affect precursor binding but stimulates the interaction of the peripheral import receptor with the core TOM complex to enable increased precursor translocation. Thus TOM70Ser91 phosphorylation by DYRK1A provides a regulatory switch for the carrier import pathway in human mitochondria. DYRK1A has not been linked to mitochondria before. Regulation of protein import by DYRK1A provides an efficient mean to adapt the mitochondrial proteome to changing cellular needs and may also build a basis for the understanding of disease mechanisms caused by dysfunctional DYRK1A.

2021-05-31 | PXD019520 | Pride

Mitoprotein-induced stress launches a global transcriptional fail-safe program

Project description:Most mitochondrial proteins are synthesized as cytosolic precursor proteins before being imported into mitochondria. Cytosolic accumulation of mitochondrial precursors hazards cellular fitness and is associated with a growing number of diseases, but is not observed under physiological conditions. Individual mechanisms how cells avoid precursor accumulation outside mitochondria have recently been discovered, but their interplay and regulation have remained elusive. Here we show that cells rapidly launch a global transcriptional program to restore cellular proteostasis after induction of a “clogger” protein that reduces the number of available mitochondrial import sites. Cells upregulate the protein folding and proteolytic systems in the cytosol and downregulate both the cytosolic translation machinery and many mitochondrial metabolic enzymes, presumably to relieve the workload of the overstrained mitochondrial import system. We show that this transcriptional remodeling is a combination of a “wideband” core response regulated by the transcription factors Hsf1 and Rpn4 and a unique mitoprotein-induced downregulation of the OXPHOS components, the most abundant group of precursors. These findings not only depict the first comprehensive model of adaptations to mitochondrial import impairment, but also reveal their regulation, connecting so far isolated stress response mechanisms into a coordinated network of cellular reactions.

2019-01-12 | GSE116749 | GEO

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

Inter-organellar and systemic survival responses to impaired mitochondrial matrix protein import in skeletal muscle

Project description:Mitochondrial functions are largely performed by proteins imported from cytosol. Impaired protein import in mitochondria affects the maintenance of intra-mitochondrial anabolic and energy metabolic pathways. It leads to cytosolic accumulation of mistargeted proteins and activation of cellular stress responses. To explore the communication between these mechanism in mammalian system, we targeted the co-chaperone of mitochondrial Hsp70, a GrpE Like protein 1 (Grpel1), in mice. We show that loss of protein import into mitochondrial matrix results in mitochondrial dysfunction, which triggers stress responses. The total shut down of mtHSP70 function by overall knockout of Grpel1 resulted in early embryonic lethality, and tamoxifen-induced skeletal muscle-specific knockout of Grpel1 caused rapid muscular atrophy. We show here, with transcriptomics analysis, that protein-import failure in mitochondria increased cellular proteotoxic stress due to mitochondrial dysfunction. As a control mechanism, it triggered adaptive stress responses, including unfolded protein responses and integrated stress responses. Metabolic profiling of skeletal muscle-specific knockout mice revealed amino acid and TCA cycle intermediates shuttle between serum and muscle.

2022-10-04 | GSE198540 | GEO

Comparative analysis of transcripts from mia40-4int mutant and wild-type Saccharomyces cerevisiae strains quantified in RNA-seq experiment

Project description:The vast majority of the mitochondrial proteome originates from nuclear genes and is transported into the organelle after synthesis in the cytosol. Complex machineries, which maintain the specificity of protein import and sorting exist. Dysfunctions of mitochondrial protein sorting pathways result in diminishing specific substrate proteins, followed by systemic pathology of the organelle and organismal death. Cellular responses that are caused by slowdown in the transport of mitochondrial proteins are unknown. Here we have used RNA-seq transcription profiling of Saccharomyces cerevisiae to uncover the changes in the cellular transcriptome in the response to mitochondrial protein import dysfunction caused by mutation in the MIA40 gene. Mia40 is a key component of the mitochondrial intermembrane import and assembly (MIA) pathway. Mia40-4int mutant used in this study is not viable at high temperatures, while in the low, permissive temperature it expresses growth rate comparable to the wild-type strain. Even during the permissive temperature culture mutant cells are characterized by decreased accumulation of MIA substrate proteins. Thus permissive growth conditions were used in the present experiment to emphasise primary responses to mitochondrial protein import defect.

2015-07-31 | E-MTAB-3588 | biostudies-arrayexpress

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