Nuclear receptor subfamily 4 group A member 1 promotes myocardial ischemia/reperfusion injury through inducing mitochondrial fission factor-mediated mitochondrial fragmentation and inhibiting FUN14 domain containing 1-depedent mitophagy

International Journal of Biological Sciences, Год журнала: 2024, Номер 20(11), С. 4458 - 4475

Опубликована: Янв. 1, 2024

This study investigated the mechanism by which NR4A1 regulates mitochondrial fission factor (Mff)-related and FUN14 domain 1 (FUNDC1)-mediated mitophagy following cardiac ischemia-reperfusion injury(I/R). Our findings showed that damage regulation was positively correlated with pathological pan-apoptosis of myocardial cell mitochondria. Compared wild-type mice (WT), NR4A1-knockout exhibited resistance to injury fission, characterized activation. Results increased expression level, activating mediated Mff restoring phenotype FUNDC1. The inactivation FUNDC1 phosphorylation could not mediate normalization in a timely manner, leading an excessive stress response unfolded proteins imbalance homeostasis. process disrupted quality control network, accumulation damaged mitochondria activation pan-apoptotic programs. data indicate is novel critical target I/R exertsand negative regulatory effects Mff-mediated mito-fission inhibiting FUNDC1-mediated mitophagy. Targeting crosstalk balance between NR4A1-Mff-FUNDC1 potential approach for treating I/R.

Язык: Английский

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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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Overcoming Fluorescence Loss in mEOS-based AAA+ Unfoldase Reporters Through Covalent Linkage

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 15, 2025

Abstract Recent work has demonstrated that the soluble photoconvertable fluorescent protein mEOS can be a reporter for AAA+ (ATPases Associated with diverse cellular Activities) unfoldase activity. Given many proteins process membrane proteins, we sought to adapt use substrates. However, direct genetic fusion of completely abolished fluorescence, severely limiting utility studying proteins. To circumvent this challenge, separately purified and degron, covalently linked them via Sortase, photoconverted construct. This innovative approach preserves fluorescence enables functional analysis, offering broadly applicable platform study associated

Язык: Английский

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Alterations in Lipid Saturation Trigger Remodeling of the Outer Mitochondrial Membrane

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 23, 2025

Lipid saturation is a key determinant of membrane function and organelle health, with changes in triggering adaptive quality control mechanisms to maintain integrity. Among cellular membranes, the mitochondrial outer (OMM) an important interface for many functions, but how lipid impacts OMM remains unclear. Here, we show that increased intracellular unsaturated fatty acids (UFAs) remodel by promoting formation multilamellar mitochondrial-derived compartments (MDCs), which sequester proteins lipids from OMM. These effects depend on incorporation UFAs into phospholipids, suggesting bilayer composition mediate this process. Furthermore, elevated impair assembly protein translocase (TOM) complex, unassembled TOM components captured MDCs. Collectively, these findings suggest alterations phospholipid may destabilize complexes trigger response excess through MDC formation. Mitochondrial-derived are structures metabolic perturbations, it largely unknown fluidity influences pathway.Increased levels phospholipids disrupt large multi-subunit complex membrane, promote compartments, while saturated inhibits compartments.These reveal link between stress driving compartment biogenesis, thus control.

Язык: Английский

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Protocol for assessing the clogging of the mitochondrial translocase of the outer membrane by precursor proteins in human cells

STAR Protocols, Год журнала: 2025, Номер 6(1), С. 103617 - 103617

Опубликована: Янв. 31, 2025

Язык: Английский

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Mitofusin 2 displays fusion-independent roles in proteostasis surveillance

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Фев. 10, 2025

Abstract Mitochondria are essential organelles and their functional state dictates cellular proteostasis. However, little is known about the molecular gatekeepers involved, especially in absence of external stress. Here we identify a role MFN2 quality control independent its function organellar shape remodeling. ablation alters proteome, marked for example by decreased levels import machinery accumulation kinase PINK1. Moreover, interacts with proteasome cytosolic chaperones, thereby preventing aggregation newly translated proteins. Similarly to MFN2-KO cells, patient fibroblasts MFN2-disease variants recapitulate excessive protein defects. Restoring re-establishes proteostasis cells rescues fusion defects MFN1-KO cells. In contrast, MFN1 loss or mitochondrial alterations do not alter aggregation, consistent fusion-independent homeostasis. sum, our findings open new possibilities therapeutic strategies modulation levels.

Язык: Английский

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Multi-omics analysis identifies OSGEPL1 as an oncogene in hepatocellular carcinoma

Discover Oncology, Год журнала: 2025, Номер 16(1)

Опубликована: Март 16, 2025

N6-Threonylcarbamoyladenosine (t6A) modification irregularities and their associated enzymes genes (OSGEP, OSGEPL1, TPRKB, GON7, TP53RK, YRDC, LAGE3) are linked to various malignancies development, including Hepatocellular Carcinoma (HCC), yet the specific mechanisms remain obscure. This gap in knowledge is significant, as understanding of t6A could reveal new insights into HCC pathogenesis potentially identify novel therapeutic targets. We leveraged data from The Cancer Genome Atlas (TCGA) analyze expression t6A-associated genes, with a focus on OSGEPL1 HCC. Our analyses included survival outcome, gene expression, functional enrichment, immune cell infiltration, somatic mutation data. discovered that upregulated correlated tumor grade, pathological T stage, overall stage. It inversely impacts infiltration. In vitro experiments confirmed role promoting proliferation. study implicates pathway dysregulation prognosis, identifying potential target. These findings provide may guide future treatment strategies.

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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Chloroplast precursor protein preClpD overaccumulation triggers multilevel reprogramming of gene expression and a heat shock-like response

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Апрель 22, 2025

Thousands of nucleus-encoded chloroplast proteins are synthesized as precursors on cytosolic ribosomes and posttranslationally imported into chloroplasts. Cytosolic accumulation unfolded precursor (e.g., under stress conditions) is hazardous to the cell. The global cellular responses regulatory pathways involved in triggering appropriate largely unknown. Here, by inducible constitutive overexpression ClpD-GFP result protein overaccumulation, we present a comprehensive picture multilevel reprogramming gene expression response overaccumulation (cPOS), reveal critical role translational activation chaperones (heat-shock proteins, HSPs), demonstrate that chloroplast-derived reactive oxygen species act retrograde signal for transcriptional small HSPs. Furthermore, an important chaperone ClpB1/HOT1 maintaining proteostasis upon cPOS. Together, our observations uncover heat shock-like cPOS provide insights underlying molecular mechanisms.

Язык: Английский

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