ArticleCell death & disease2014
Mitochondrial proteolytic stress induced by loss of mortalin function is rescued by Parkin and PINK1.
Article in Cell death & disease, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers.
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Who cites it
59 citing papers in PubMed, 99 citations in OpenAlex.
- Mapping the global research landscape of mitophagy in Parkinson's disease: a bibliometric and visualization analysis.Hereditas · 2025Article
- Mortalin and PINK1/Parkin-Mediated Mitophagy Represent Ovarian Cancer-Selective Targets for Drug Development.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- The Regulation of the Disease-Causing GeneCells · 2024Review
- A-Syn(ful) MAM: A Fresh Perspective on a Converging Domain in Parkinson's Disease.International journal of molecular sciences · 2024Review
- Collective heterogeneity of mitochondrial potential in contact inhibition of proliferation.Biophysical journal · 2023Article
- Chronic Cerebral Hypoperfusion-Induced Disturbed Proteostasis of Mitochondria and MAM Is Reflected in the CSF of Rats by Proteomic Analysis.Molecular neurobiology · 2023Article
- Article
- Enhanced primary ciliogenesis via mitochondrial oxidative stress activates AKT to prevent neurotoxicity in HSPA9/mortalin-depleted SH-SY5Y cells.Molecular brain · 2023Article
- ATF5 regulates tubulointerstitial injury in diabetic kidney disease via mitochondrial unfolded protein response.Molecular medicine (Cambridge, Mass.) · 2023Article
- Exercise Improves the Coordination of the Mitochondrial Unfolded Protein Response and Mitophagy in Aging Skeletal Muscle.Life (Basel, Switzerland) · 2023Review
- Mortalin/Hspa9 involvement and therapeutic perspective in Parkinson's disease.Neural regeneration research · 2023Review
- Mortalin: Protein partners, biological impacts, pathological roles, and therapeutic opportunities.Frontiers in cell and developmental biology · 2023Review
- Diversity of mitophagy pathways at a glance.Journal of cell science · 2022Article
- In Silico Identification of Multi-Target Ligands as Promising Hit Compounds for Neurodegenerative Diseases Drug Development.International journal of molecular sciences · 2022Article
- PolyGA targets the ER stress-adaptive response by impairing GRP75 function at the MAM in C9ORF72-ALS/FTD.Acta neuropathologica · 2022Article
- Protein import motor complex reacts to mitochondrial misfolding by reducing protein import and activating mitophagy.Nature communications · 2022Article
- Pleiotropic effects of mitochondria in aging.Nature aging · 2022Review
- PINK1-Dependent Mitophagy Reduced Endothelial Hyperpermeability and Cell Migration Capacity Under Simulated Microgravity.Frontiers in cell and developmental biology · 2022Article
- Altered Mitochondrial Protein Homeostasis and Proteinopathies.Frontiers in molecular neuroscience · 2022Review
- Insights Into the Role of Mortalin in Alzheimer's Disease, Parkinson's Disease, and HIV-1-Associated Neurocognitive Disorders.Frontiers in cell and developmental biology · 2022Review
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Authors and funding
15 authors at 5 institutions in 2 countries.
Funding
Abstract
The mitochondrial chaperone mortalin was implicated in Parkinson's disease (PD) because of its reduced levels in the brains of PD patients and disease-associated rare genetic variants that failed to rescue impaired mitochondrial integrity in cellular knockdown models. To uncover the molecular mechanisms underlying mortalin-related neurodegeneration, we dissected the cellular surveillance mechanisms related to mitochondrial quality control, defined the effects of reduced mortalin function at the molecular and cellular levels and investigated the functional interaction of mortalin with Parkin and PINK1, two PD-related proteins involved in mitochondrial homeostasis. We found that reduced mortalin function leads to: (1) activation of the mitochondrial unfolded protein response (UPR(mt)), (2) increased susceptibility towards intramitochondrial proteolytic stress, (3) increased autophagic degradation of fragmented mitochondria and (4) reduced mitochondrial mass in human cells in vitro and ex vivo. These alterations caused increased vulnerability toward apoptotic cell death. Proteotoxic perturbations induced by either partial loss of mortalin or chemical induction were rescued by complementation with native mortalin, but not disease-associated mortalin variants, and were independent of the integrity of autophagic pathways. However, Parkin and PINK1 rescued loss of mortalin phenotypes via increased lysosomal-mediated mitochondrial clearance and required intact autophagic machinery. Our results on loss of mortalin function reveal a direct link between impaired mitochondrial proteostasis, UPR(mt) and PD and show that effective removal of dysfunctional mitochondria via either genetic (PINK1 and Parkin overexpression) or pharmacological intervention (rapamycin) may compensate mitochondrial phenotypes.
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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.