Mitochondrial YME1L1 governs unoccupied protein translocase channels

Nature Cell Biology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 7, 2025

Язык: Английский

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Mitochondrial protein import stress

Nature Cell Biology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 22, 2025

Язык: Английский

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ATAD1 prevents clogging of TOM and damage caused by un-imported mitochondrial proteins

Cell Reports, Год журнала: 2024, Номер 43(8), С. 114473 - 114473

Опубликована: Июль 17, 2024

Язык: Английский

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Diverse routes to mitophagy governed by ubiquitylation and mitochondrial import

Trends in Cell Biology, Год журнала: 2025, Номер unknown

Опубликована: Фев. 1, 2025

HighlightsStructural and biochemical studies of PINK1 activation stabilisation have captured TOM complex interactions the formation a PINK1–TOM–TIM supercomplex.USP30 inhibition shows promising preclinical indications.FBXL4 is major suppressor NIX/BNIP3-dependent mitophagy.PPTC7 scaffolds interaction FBXL4–SCF ligase with BNIP3 NIX.Control PPTC7 mitochondrial import sets levels NIX.AbstractThe selective removal mitochondria by mitophagy proceeds via multiple mechanisms essential for human well-being. The PINK1/Parkin NIX/BNIP3 pathways are strongly linked to dysfunction hypoxia, respectively. Both regulated ubiquitylation import. Recent elucidated how ubiquitin kinase acts as sensor stress through stable supercomplex. stability NIX SCFFBXL4 complex. Substrate recognition requires an adaptor molecule, PPTC7, whose availability limited Unravelling functional implications each mode remains critical challenge. We propose that prompts switch between these two pathways.

Язык: Английский

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Conserved quality control mechanisms of mitochondrial protein import

Journal of Inherited Metabolic Disease, Год журнала: 2024, Номер 47(5), С. 903 - 916

Опубликована: Май 24, 2024

Mitochondria carry out essential functions for the cell, including energy production, various biosynthesis pathways, formation of co-factors and cellular signalling in apoptosis inflammation. The functionality mitochondria requires import about 900-1300 proteins from cytosol baker's yeast Saccharomyces cerevisiae human cells, respectively. vast majority these pass outer membrane a largely unfolded state through translocase mitochondrial (TOM) complex. Subsequently, specific protein translocases sort precursor into inner membranes, intermembrane space matrix. Premature folding proteins, defects or reduction potential across can cause stalling precursors at apparatus. Consequently, translocon is clogged non-imported accumulate which turn leads to proteotoxic stress eventually cell death. To prevent such situations, quality control mechanisms remove TOM channel. highly conserved ubiquitin-proteasome system plays critical role this process. Thus, surveillance via complex involves coordinated activity mitochondria-localized cytosolic cell.

Язык: Английский

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Hypotonic Swelling Method for the Isolation of Pure Mitochondria From Primary Human Skeletal Myoblasts for Proteomic Studies

Journal of Cellular and Molecular Medicine, Год журнала: 2025, Номер 29(2)

Опубликована: Янв. 1, 2025

ABSTRACT Mitochondria play a fundamental role in energy metabolism, particularly high‐energy‐demand tissues such as skeletal muscle. Understanding the proteomic composition of mitochondria these cells is crucial for elucidating mechanisms underlying muscle physiology and pathology. However, effective isolation from primary human has been challenging due to complex cellular architecture propensity contamination with other organelles. Here, we compared four different methods isolate myoblasts regarding total protein yield, mitochondrial enrichment capacity purity isolated fraction. We presented modified method that combines differential centrifugation hypotonic swelling step subsequent purification process minimise contamination. validated our by demonstrating its ability obtain highly pure fractions, confirmed Western Blot mitochondrial, cytosolic nuclear markers. demonstrated analysis can be performed mitochondria. Our approach provides valuable tool investigating dynamics, biogenesis function context biology health disease. This methodological advancement opens new avenues research implications myopathies, sarcopenia, cachexia metabolic disorders.

Язык: Английский

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A long-lived pool of PINK1 imparts a molecular memory of depolarization-induced activity

Science Advances, Год журнала: 2025, Номер 11(9)

Опубликована: Фев. 28, 2025

The Parkinson’s disease–linked kinase, PINK1, is a short-lived protein that undergoes cleavage upon mitochondrial import leading to its proteasomal degradation. Under depolarizing conditions, it accumulates on mitochondria where becomes activated, phosphorylating both ubiquitin and the E3 ligase Parkin, at Ser 65 . Our experiments reveal in retinal pigment epithelial cells, only fraction of PINK1 stabilized after depolarization by electron transport chain inhibitors. Furthermore, observed accrual cannot be completely accounted for without an accompanying increase biosynthesis. We have used ubiquitylation inhibitor TAK-243 accumulate cleaved PINK1. these generation unconjugated “free” phospho-ubiquitin serves as proxy readout activity. This has enabled us find preconditioning phenomenon, whereby initial treatment leaves residual pool active remains competent seed activation nascent following 16-hour recovery period.

Язык: Английский

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Unclogging of the TOM complex under import stress

Biological Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Март 28, 2025

Abstract Mitochondrial functions and biogenesis depend on the import of more than 1,000 proteins which are synthesized as precursor cytosolic ribosomes. protein translocases sort into mitochondrial sub-compartments: outer inner membrane, intermembrane space matrix. The translocase membrane (TOM complex) constitutes major site for most these proteins. Defective translocases, premature folding precursor, or depletion potential can cause clogging TOM channel by a protein. This impairs further leads to accumulation in cell that perturbates homeostasis, leading proteotoxic stress cell. Therefore, unclogging translocon is critical maintaining cellular function. Ubiquitylation AAA-ATPases play central role extraction deliver them proteasome degradation. Here we summarize our understanding molecular mechanisms remove such translocation-stalled from translocation regenerate complex import.

Язык: Английский

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Illuminating plant metabolism with genetically encoded biosensors

Journal of Plant Physiology, Год журнала: 2025, Номер unknown, С. 154498 - 154498

Опубликована: Апрель 1, 2025

Язык: Английский

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OMA1 clears traffic jam in TOM tunnel in mammals

The Journal of Cell Biology, Год журнала: 2024, Номер 223(5)

Опубликована: Апрель 15, 2024

Using an engineered mitochondrial clogger, Krakowczyk et al. (https://doi.org/10.1083/jcb.202306051) identified the OMA1 protease as a critical component that eliminates import failure at TOM translocase in mammalian cells, providing novel quality control mechanism is distinct from those described yeast.

Язык: Английский

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