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An Early mtUPR: Redistribution of the Nuclear Transcription Factor Rox1 to Mitochondria Protects against Intramitochondrial Proteotoxic Aggregates.

ABSTRACT: The mitochondrial proteome is built mainly by import of nuclear-encoded precursors, which are targeted mostly by cleavable presequences. Presequence processing upon import is essential for proteostasis and survival, but the consequences of dysfunctional protein maturation are unknown. We find that impaired presequence processing causes accumulation of precursors inside mitochondria that form aggregates, which escape degradation and unexpectedly do not cause cell death. Instead, cells survive via activation of a mitochondrial unfolded protein response (mtUPR)-like pathway that is triggered very early after precursor accumulation. In contrast to classical stress pathways, this immediate response maintains mitochondrial protein import, membrane potential, and translation through translocation of the nuclear HMG-box transcription factor Rox1 to mitochondria. Rox1 binds mtDNA and performs a TFAM-like function pivotal for transcription and translation. Induction of early mtUPR provides a reversible stress model to mechanistically dissect the initial steps in mtUPR pathways with the stressTFAM Rox1 as the first line of defense.

SUBMITTER: Poveda-Huertes D

PROVIDER: S-EPMC6941230 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Author's View: a nuclear transcription factor relocalizing to mitochondria rescues cells from proteotoxic aggregates.

Project description:Mitochondrial proteostasis is essential for survival, and imbalances can result in severe human diseases. We identified a novel stress response triggered upon accumulation of proteotoxic aggregates in the mitochondrial matrix. Mitochondria-to-nucleus signaling results in a transcriptional response and translocation of a nuclear transcription factor into mitochondria to maintain mitochondrial gene expression.

| S-EPMC6961659 | biostudies-literature

Distinct types of intramitochondrial protein aggregates protect mitochondria against proteotoxic stress - Data Set5: TMT dataset of aggregates in mitochondria

Project description:Mitochondria consist of hundreds of proteins, most of which are long-lived and inaccessible to the proteasomal quality control system of the cytosol. How cells stabilize the mitochondrial proteome during challenging conditions is poorly understood. Here we show that mitochondria form spatially defined protein aggregates as a stress-protecting mechanism. Thereby different types of intramitochondrial protein aggregates can be distinguished. The mitoribosomal protein Var1 (uS3m) undergoes a stress-induced transition from a soluble, chaperone-stabilized protein that is prevalent under benign conditions to an insoluble aggregated form upon acute stress. The formation of Var1 bodies stabilizes mitochondrial proteostasis presumably by sequestration of aggregation-prone proteins. The AAA chaperone Hsp78 associates with a different type of intramitochondrial aggregate. These Hsp78-bound aggregates sequester non-native matrix proteins to promote their subsequent folding or Pim1-mediated degradation. Our study shows that mitochondrial proteins actively control the formation of different types of intramitochondrial protein aggregates which actively cooperate to stabilize the mitochondrial proteome during proteotoxic stress conditions.

2024-03-26 | PXD048691 | Pride

Distinct types of intramitochondrial protein aggregates protect mitochondria against proteotoxic stress - Data Set1: HSP78 AP-MS

2024-03-26 | PXD045196 | Pride

Distinct types of intramitochondrial protein aggregates protect mitochondria against proteotoxic stress - Data Set2: PIM1 AP-MS

2024-03-26 | PXD045286 | Pride

Distinct types of intramitochondrial protein aggregates protect mitochondria against proteotoxic stress - Data Set3: VAR1 AP-MS

2024-03-26 | PXD045288 | Pride

Syncytial nuclear aggregates in normal placenta show increased nuclear condensation, but apoptosis and cytoskeletal redistribution are uncommon.

Project description:INTRODUCTION: Syncytial nuclear aggregates (SNAs) are increased in pregnancy complications; however, little is known about their origin or function. This study aimed to characterise SNAs in more detail than has been reported previously. METHODS: Immunohistochemistry and morphological examination at the light and ultrastructural level were used to determine the nature and structure of SNAs. RESULTS: SNAs comprising bridges and syncytial knots had similar frequency with 974 per mm3 of villous tissue (IQR 717-1193) and 833 per mm3 (IQR 766-1190), respectively while there were approximately four times as many sectioning artefacts than knots and bridges combined. SNAs had increased proportions of condensed nuclei compared to the remaining syncytiotrophoblast (33.3% vs. 8.9%) and decreased proportions of euchromatic nuclei (0.0% vs. 16.2%), as assessed by examination of an electron micrograph archive. SNAs showed little evidence of apoptosis, with weak positivity for the apoptosis markers M30-neoepitope at 16.6% and TUNEL at 10.0%; strong staining was rarely seen for either marker. Immunofluorescence demonstrated rare association of actin (?, ? or ?) with SNAs, whereas tubulin was in close proximity to SNAs and cytokeratin was seen within and surrounding SNAs. DISCUSSION: M30-positive SNAs traced through serial sections were significantly more likely to be syncytial knots or sectioning artefacts than bridges. Nuclei within SNAs showed signs consistent with degeneration; however, this is unlikely to be an apoptotic process. There are few changes in configuration of cytoskeletal proteins around SNAs. CONCLUSIONS: These data suggest that the biogenesis and functional significance of SNAs still require resolution.

| S-EPMC3661987 | biostudies-literature

Distinct types of intramitochondrial protein aggregates protect mitochondria against proteotoxic stress - Data Set4: Total proteome of NTS-VAR1 expressing yeast cells

2024-03-26 | PXD045290 | Pride

NEDDylation promotes nuclear protein aggregation and protects the Ubiquitin Proteasome System upon proteotoxic stress.

Project description:Spatial management of stress-induced protein aggregation is an integral part of the proteostasis network. Protein modification by the ubiquitin-like molecule NEDD8 increases upon proteotoxic stress and it is characterised by the formation of hybrid NEDD8/ubiquitin conjugates. However, the biological significance of this response is unclear. Combination of quantitative proteomics with biological analysis shows that, during proteotoxic stress, NEDDylation promotes nuclear protein aggregation, including ribosomal proteins as a major group. This correlates with protection of the nuclear Ubiquitin Proteasome System from stress-induced dysfunction. Correspondingly, we show that NEDD8 compromises ubiquitination and prevents targeting and processing of substrates by the proteasome. Moreover, we identify HUWE1 as a key E3-ligase that is specifically required for NEDDylation during proteotoxic stress. The study reveals a specific role for NEDD8 in nuclear protein aggregation upon stress and is consistent with the concept that transient aggregate formation is part of a defence mechanism against proteotoxicity.

| S-EPMC6197266 | biostudies-literature

FOXM1 nuclear transcription factor translocates into mitochondria and inhibits oxidative phosphorylation.

Project description:Forkhead box M1 (FOXM1), a nuclear transcription factor that activates cell cycle regulatory genes, is highly expressed in a majority of human cancers. The function of FOXM1 independent of nuclear transcription is unknown. In the present study, we found the FOXM1 protein inside the mitochondria. Using site-directed mutagenesis, we generated FOXM1 mutant proteins that localized to distinct cellular compartments, uncoupling the nuclear and mitochondrial functions of FOXM1. Directing FOXM1 into the mitochondria decreased mitochondrial mass, membrane potential, respiration, and electron transport chain (ETC) activity. In mitochondria, the FOXM1 directly bound to and increased the pentatricopeptide repeat domain 1 (PTCD1) protein, a mitochondrial leucine-specific tRNA binding protein that inhibits leucine-rich ETC complexes. Mitochondrial FOXM1 did not change cellular proliferation. Thus, FOXM1 translocates into mitochondria and inhibits mitochondrial respiration by increasing PTCD1. We identify a new paradigm that FOXM1 regulates mitochondrial homeostasis in a process independent of nuclear transcription.

| S-EPMC7353143 | biostudies-literature

Proteotoxic stress increases nuclear localization of ataxin-3.

Project description:Spinocerebellar ataxia type 3 (SCA3)/Machado Joseph disease results from expansion of the polyglutamine domain in ataxin-3 (Atx3). Atx3 is a transcriptional co-repressor, as well as a deubiquitinating enzyme that appears to function in cellular pathways involved in protein homeostasis. In this study, we show that interactions of Atx3 with valosin-containing protein and hHR23B are dynamic and modulated by proteotoxic stresses. Heat shock, a general proteotoxic stress, also induced wild-type and pathogenic Atx3 to accumulate in the nucleus. Mapping studies showed that two regions of Atx3, the Josephin domain and the C-terminus, regulated heat shock-induced nuclear localization. Heat shock-induced nuclear localization of Atx3 was not affected by a casein kinase-2 inhibitor or by mutating a predicted nuclear localization signal. However, serine-111 of Atx3 was required for nuclear localization of the Josephin domain and regulated nuclear localization of full-length Atx3. Atx3 null cells were more sensitive to toxic effects of heat shock suggesting that Atx3 had a protective function in the cellular response to heat shock. Importantly, we found that oxidative stress also induced nuclear localization of Atx3; both wild-type and pathogenic Atx3 accumulated in the nucleus of SCA3 patient fibroblasts following oxidative stress. Heat shock and oxidative stress are the first processes identified that increase nuclear localization of Atx3. Observations in this study provide new and important insights for understanding SCA3 pathology as the nucleus is likely a key site for early pathogenesis.

| S-EPMC2796889 | biostudies-other

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