Context-Dependent Roles of Mitochondrial LONP1 in Orchestrating the Balance between Airway Progenitor versus Progeny Cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA958384 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24258425_1.fastq.gz | Fastqsanger.gz | |||
| SRR24258425_2.fastq.gz | Fastqsanger.gz | |||
| SRR24258426_1.fastq.gz | Fastqsanger.gz | |||
| SRR24258426_2.fastq.gz | Fastqsanger.gz | |||
| SRR24258427_1.fastq.gz | Fastqsanger.gz |
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Project description:While all eukaryotic cells are dependent on mitochondria for function, in a complex tissue, which cell type and which cell behavior are more sensitive to mitochondrial deficiency remains unpredictable. Here we show that in the mouse airway, compromising mitochondrial function by inactivating mitochondrial protease gene Lonp1 led to reduced progenitor proliferation and differentiation during development; apoptosis of terminally differentiated ciliated cells and their replacement by basal progenitors and goblet cells during homeostasis; and failed airway progenitor migration into damaged alveoli following influenza infection. ATF4 and the integrated stress response (ISR) pathway are elevated and responsible for airway phenotypes. Such context dependent sensitivities are predicted by the selective expression of Bok, which is required for ISR activation. Reduced LONP1 expression is found in chronic obstructive pulmonary disease (COPD) airways with squamous metaplasia. These findings illustrate a cellular energy landscape whereby compromised mitochondrial function could favor the emergence of pathological cell types.
2024-08-23 | GSE230334 | GEO
Project description:Studying the molecular basis for the skeletal muscle mitochondrial stress response could potentially be targeted to counteract metabolic disorders such as obesity. We uncovered a crucial role for the mitochondrial protease LONP1 in controlling the muscle mitochondrial proteostasis stress response that governs systemic metabolic homeostasis. Skeletal muscle-specific ablation of LONP1 led to broad genomic reprogramming of muscle and protected the mice from HFD-induced obesity. To thoroughly analyze pathways that are affected by ATF4 deficiency in the context of LONP1 mKO, we performed RNA-Seq transcriptome analysis of skeletal muscles from WT, LONP1 mKO and LONP1ATF4 DmKO mice. We identified a total of 3017 differentially expressed genes with a cutoff of 1.5-fold, and p < 0.05. Surprisingly, we found that ATF4 loss blunted a subset of regulated genes in LONP1 mKO muscles, whereas the majority of differentially regulated genes in LONP1 mKO muscles were not affected by ATF4 ablation. GO analysis of ATF4-dependent genes regulated by LONP1 ablation revealed significant enrichment in amino acid metabolic processes, Interestingly, however, LONP1 deficiency induced activation of muscle UPR and UPR-related RNA processing as well as myokine pathways were not affected by ATF4 ablation. Therefore, our results highlight a ATF4-independent mechanism in mediating the UPRmt in mammals.
2022-07-28 | GSE192990 | GEO
Project description:Mitochondria serve diverse functions and are essential organelles that require continuous surveillance to maintaintheir integrity and function. LONP1 is an evolutionarily conservedserine peptidase that safeguards mitochondrial protein quality from yeast to human.To investigatethe physiological role of LONP1-mediated mitochondrial quality-control in skeletal musclein vivo, we generated skeletal muscle-specificLonp1-knockout mice (referred to as LONP1 MKO). We performedtranscriptome analysis by whole-genome gene expression profiling experiments in gastrocnemius (GC) muscle from both wild-type (WT) and LONP1-MKO mice. Knockout of LONP1 in skeletal muscle resulted in deregulation of 457 genes in 2-week-old mice and of 1922 genes in 6-week-old mice. Gene ontology analysis revealed that LONP1 deficiency triggers unfolded protein response (UPR) in skeletal muscle.Moreover, GSEA analysis of transcriptomic datain 6-week-old micefurther revealed that genes deregulated by LONP1 deficiency were significantly enriched during aging.Together, the transcriptional profiling results suggest a critical role of LONP1 in regulating skeletal muscle metabolism and health.
2022-01-05 | GSE166071 | GEO
Project description:Mitochondrial proteases are emerging as key regulators of mitochondrial plasticity acting both as protein quality surveillance and regulatory enzymes by performing highly regulated proteolytic reactions. It remains unclear, however, whether the regulated mitochondrial proteolysis is mechanistically linked to cell identity switch such as white-to-beige conversion of adipocytes. We found that disruption of LONP1-dependent proteolysis substantially impairs thermogenic molecular program and cellular respiration in in vitro differentiated primary adipocytes. qPCR analysis showed that expression levels of Ucp1 and other beige adipocyte thermogenic genes were remarkably downregulated in LONP1 AKO adipocytes. We took a deeper dive into the characterization of histone modifications in LONP1 AKO adipocytes using the global enhancer marker H3K4me1 ChIP-Seq. These unbiased ChIP seq data are strong evidence of that LONP1 loss results in decreased H3K4me1 on a broad array of thermogenic genes. These results collectively indicate that LONP1 is crucial to maintain proper epigenetic homeostasis and beige thermogenic gene expression.
2023-04-08 | GSE222490 | GEO
Project description:Lon protease 1 (LONP1) is an ATP-dependent protease located in the mitochondrial matrix and plays a crucial role in regulating mitochondrial proteostasis, metabolism and cellular stress responses. Here we show that overexpression of LONP1 is closely related to adverse clinicopathological features and poor prognosis in prostate cancer (PCa) patients. Mechanistically, the findings reveal that LONP1 is implicated in modulating the metabolic switch from oxidative phosphorylation (OXPHOS) to aerobic glycolysis, thereby promoting tumor proliferation, invasion and metastasis both in vitro and in vivo. Meanwhile, we prove that LONP1 as a protease directly targets mitochondrial pyruvate carrier 1 (MPC1), a key metabolic protein in the process of glycolysis, and enhances its degradation, which in turn suppresses tricarboxylic acid (TCA) cycle and ultimately promotes the progression of PCa. Furthermore, using PCa in cancer-prone mice homozygous for a prostate-targeted conditional Pten knockout and Lonp1 knockin, we integrate transcriptomic and proteomic analyses of prostate tumors, upon which reveals that Lonp1 overexpression results in a significant downregulation of NADH: ubiquinone oxidoreductase activity, consequently impeding the electron transfer process and mitochondrial ATP synthesis, associated with metastasis of PCa. Collectively, our results highlight that metabolic reprogramming induced by LONP1 in PCa is closely coupled with disease progression, suggesting that targeting the LONP1-mediated cascade in the mitochondrial may provide therapeutic potential for PCa disease.
2025-02-26 | GSE268736 | GEO
Project description:We analyzed the effects of Lonp1 silencing on the response to heat shock by analyzing the transriptomic profile of SW620 colon cancer cells undergoing heat shock. Briefly, Lonp1 has been silenced by using a specific siRNA, then cells have been kept at 42°C for 1 hour, and left at 37°C for one hour.
2022-06-28 | GSE164834 | GEO
Project description:The mechanisms of hepatic stellate cell (HSC) activation and the development of liver fibrosis remains largely unknow. Here, we revealed a fibrosis related mechanism of hepatocytes-HSCs crosstalk regulated by hepatocyte LONP1. We demonstrate that hepatocyte LONP1 expression is decreased in HFD-fed mice and MASH patients. Liver-specific LONP1 deficiency increases orotic acid level and aggravates MASH-induced liver fibrosis in mice. We have identified DHODH as a substrate that is selectively degraded by LONP1 in an ATP-dependent manner. Moreover, activation of LONP1 reduces orotic acid levels and alleviates MASH-induced fibrosis in mice. Mechanistically, LONP1 mediates DHODH turnover, maintaining lower orotic acid levels to inhibit ATF3-mediated HSC proliferation and activation, thereby preventing liver fibrosis. Furthermore, plasma orotic acid levels are negatively correlated with liver LONP1 levels in humans. Therefore, targeting LONP1-mediated hepatocyte-HSC communication may represent a promising therapeutic strategy for MASH-induced liver fibrosis.
2025-09-23 | PXD055467 | Pride
Project description:Because 99% of the mitochondrial proteome is encoded by the nucleus, most mitochondrial precursor polypeptides are imported from the cytosol into the mitochondrion, where they must efficiently fold into their functional state. Mitochondrial precursors are imported as unfolded polypeptides due to the limited pore size of the import machinery. For proteins of the mitochondrial matrix and inner membrane, two separate and highly conserved chaperone systems, HSP60 and mitochondrial HSP70 (mtHSP70), facilitate protein folding. Here we show that LONP1, a AAA+ protease of the mitochondrial matrix, works with the mtHSP70 chaperone system to promote mitochondrial protein folding. Inhibition of LONP1 results in aggregation of a protein subset similar to that caused by knockdown of DNAJA3, a co-chaperone of mtHSP70. LONP1 is required for DNAJA3 and mtHSP70 solubility, and its ATPase, but not its protease activity, is required for this function. In vitro, LONP1 collaborates with mtHSP70 and its co-factors to stabilize a folding intermediate of OXA1L. In the absence of LONP1, the interaction of mtHSP70 with OXA1L is futile and results in substrate-induced coaggregation. Our results identify mitochondrial LONP1 as a critical factor in the mtHSP70 folding pathway and directly demonstrate its long suspected chaperone activity.
2020-12-07 | PXD021939 | Pride
Project description:It is documented that intracellular succinate levels are maintained and regulated by mitochondrial complexes II. In order to define the LONP1-dependent regulators of succinate content, unbiased TurboID-based proximity labeling was employed to exploit LONP1-targeting proteins. Our results showed that 63.5% of the proteins identified by LONP1-N-TurboID-based proximity labeling are mitochondrial proteins. Functional protein association networks analysis of the identified proteins indicated that these biotinylated proteins are related to carboxylic acid metabolic process, mitochondrial organization and mitochondrial gene expression.
2023-04-08 | PXD031197 | Pride
Project description:The mitochondrial matrix protease LONP1 is an essential part of the organellar protein quality control system. LONP1 has been shown to be involved in respiration control and apoptosis. Furthermore, a reduction in LONP1 level correlates with ageing processes. Up to now, the effects of a LONP1 defect were mostly studied by utilizing transient, siRNA-mediated knockdown approaches. We generated a new cellular model system for studying the impact of LONP1 on mitochondrial protein homeostasis by a CRISPR/Cas-mediated genetic knockdown (gKD). These cells show a stable reduction of LONP1 along with a mild phenotype characterized by absent morphological differences and only small negative effects on mitochondrial functions under normal culture conditions. To assess the consequences of a permanent LONP1 depletion on the mitochondrial proteome, we analyzed the alterations of protein levels by quantitative mass spectrometry, demonstrating small adaptive changes, in particular concerning mitochondrial protein biogenesis. In an additional proteomic analysis, we determined the temperature-dependent aggregation behavior of mitochondrial proteins and its dependence on a reduction of LONP1 activity, demonstrating the important role of the protease for mitochondrial protein homeostasis in mammalian cells. We identified a significant number of mitochondrial proteins that are affected by LONP1 activity concerning their stressinduced solubility. Taken together, our results suggest a very good applicability of the LONP1 gKD cell line as a model system for human ageing processes.
2022-01-31 | PXD026941 | Pride