ArticleOncogenesis2021
LONP1 and ClpP cooperatively regulate mitochondrial proteostasis for cancer cell survival.
Article in Oncogenesis, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
What it found
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The trial behind it
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Who cites it
46 citing papers in PubMed, 70 citations in OpenAlex.
- A selective inhibitor reveals roles for LONP1 in mitochondrial proteostasis and OXPHOS dependencies.Life science alliance · 2026Article
- Elucidating the Molecular Impact of DA29-Induced ClpP Chemoactivation on Mitochondrial Function.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- Deciphering LonP1's role in glioblastoma: an alternative mechanism of treatment resistance.American journal of physiology. Cell physiology · 2026Article
- A multilayered stress-response circuit: The mammalian mitochondrial UPR.The FEBS journal · 2026Review
- The mitochondrial protease, LonP1, is a potential cardioprotective target for attenuating doxorubicin-induced cardiomyocyte death.Journal of translational medicine · 2026Article
- Reprogramming Mitochondrial Adaptation: LONP1 at the Crossroads of Proteostasis, Metabolism, and Disease.Antioxidants (Basel, Switzerland) · 2026Review
- Downregulation of Lonp1 Promotes Melanocyte Pyroptosis via Suppressing Mitophagy and Activating NLRP3 Pathway in Vitiligo under Oxidative Stress.Inflammation · 2026Article
- Copper homeostasis and cuproptosis in cancer: mitochondrial metabolic dependency and nanomedicine-based therapeutic strategies.Apoptosis : an international journal on programmed cell death · 2026Review
- Molecular mechanisms of mitochondrial AAA+ proteases.The Journal of biological chemistry · 2026Review
- Development and evaluation of mitochondria-targeted caseinolytic protease (ClpP) agonist chemical probes in in vitro breast cancer models.Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents · 2026Article
- Mitochondrial Metabolic Reprogramming in Macrophages: A Key Driver of Rheumatoid Arthritis.Journal of inflammation research · 2026Review
- Dual role of HIF-1α in gliomas: enhancing COX7A2 degradation and SCAF1 expression for ATP production and tumor progression.American journal of cancer research · 2026Article
- Identifying a novel Mecp2-mediated epigenetic mechanism controlling Lonp1 in the hippocampus and its disruption by aging.Scientific reports · 2025Article
- Identification of genes related to the effects of bicalutamide and zoladex on benign prostatic hyperplasia.Scientific reports · 2025Article
- Mitochondrial Protease ClpP: Cancer Marker and Drug Target.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Article
- Targeting mitochondrial proteases CLPP and LONP1 via disruption of mitochondrial redox homeostasis induces proteotoxic stress and suppresses tumor progression.Cell communication and signaling : CCS · 2025Article
- Multifaceted role of serine hydroxymethyltransferase in health and disease.Molecules and cells · 2025Review
- Mitochondrial metabolism and cancer therapeutic innovation.Signal transduction and targeted therapy · 2025Review
- Article
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
Mitochondrial proteases are key components in mitochondrial stress responses that maintain proteostasis and mitochondrial integrity in harsh environmental conditions, which leads to the acquisition of aggressive phenotypes, including chemoresistance and metastasis. However, the molecular mechanisms and exact role of mitochondrial proteases in cancer remain largely unexplored. Here, we identified functional crosstalk between LONP1 and ClpP, which are two mitochondrial matrix proteases that cooperate to attenuate proteotoxic stress and protect mitochondrial functions for cancer cell survival. LONP1 and ClpP genes closely localized on chromosome 19 and were co-expressed at high levels in most human cancers. Depletion of both genes synergistically attenuated cancer cell growth and induced cell death due to impaired mitochondrial functions and increased oxidative stress. Using mitochondrial matrix proteomic analysis with an engineered peroxidase (APEX)-mediated proximity biotinylation method, we identified the specific target substrates of these proteases, which were crucial components of mitochondrial functions, including oxidative phosphorylation, the TCA cycle, and amino acid and lipid metabolism. Furthermore, we found that LONP1 and ClpP shared many substrates, including serine hydroxymethyltransferase 2 (SHMT2). Inhibition of both LONP1 and ClpP additively increased the amount of unfolded SHMT2 protein and enhanced sensitivity to SHMT2 inhibitor, resulting in significantly reduced cell growth and increased cell death under metabolic stress. Additionally, prostate cancer patients with higher LONP1 and ClpP expression exhibited poorer survival. These results suggest that interventions targeting the mitochondrial proteostasis network via LONP1 and ClpP could be potential therapeutic strategies for cancer.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.