ArticleHuman molecular genetics2021
Mitochondria-lysosome membrane contacts are defective in GDAP1-related Charcot-Marie-Tooth disease.
Article in Human molecular genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers, 1 of them a synthesis that pooled it.
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Who cites it
49 citing papers in PubMed, 1 synthesis or guideline pooled it, 66 citations in OpenAlex.
- Inter-organellar Communication in Parkinson's and Alzheimer's Disease: Looking Beyond Endoplasmic Reticulum-Mitochondria Contact Sites.Frontiers in neuroscience · 2022Pooled it
- Mitochondrial interplay with membrane organelles in health and disease.Cell communication and signaling : CCS · 2026Review
- Unraveling GDAP1: Bridging Mitochondrial Biology and Peripheral Neuropathy.Biomolecules · 2026Review
- Smart Nanoparticles Disrupting Energy Supply through Triple Mechanisms to Kill Tumors via Dual Disruption of Mitochondria and Lysosomes.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Focusing on microglial mitochondria-lysosome crosstalk and neuroinflammation underlying depression: from molecular pathways to potential therapeutic interventions.Frontiers in immunology · 2026Review
- Potential Role of Membrane Contact Sites in the Dysregulation of the Crosstalk Between Mitochondria and Lysosomes in Alzheimer's Disease.International journal of molecular sciences · 2025Review
- BDH2-driven lysosome-to-mitochondria iron transfer shapes ferroptosis vulnerability of the melanoma cell states.Nature metabolism · 2025Article
- Article
- Charcot Marie Tooth disease pathology is associated with mitochondrial dysfunction and lower glutathione production.Cellular and molecular life sciences : CMLS · 2025Article
- Lysosome-Mitochondrial Crosstalk in Cellular Stress and Disease.Antioxidants (Basel, Switzerland) · 2025Review
- Deficiency in NPC2 results in disruption of mitochondria-late endosome/lysosomes contact sites and endo-lysosomal lipid dyshomeostasis.Scientific reports · 2025Article
- Role of lipids in interorganelle communication.Trends in cell biology · 2025Review
- Mitochondrial dysfunction, cause or consequence in neurodegenerative diseases?BioEssays : news and reviews in molecular, cellular and developmental biology · 2025Review
- Biological Basis of Cell Trafficking: A General Overview.Journal of inherited metabolic disease · 2025Review
- Abnormal redox balance at membrane contact sites causes axonopathy inResearch square · 2024Article
- A Role of Inflammation in Charcot-Marie-Tooth Disorders-In a Perspective of Treatment?International journal of molecular sciences · 2024Review
- Ethnicity-related differences in mitochondrial regulation by insulin stimulation in diabetes.Journal of cellular physiology · 2024Review
- Lysosomal dysfunction and overload of nucleosides in thymidine phosphorylase deficiency of MNGIE.Journal of translational medicine · 2024Article
- A SPLICS reporter reveals [Formula: see text]-synuclein regulation of lysosome-mitochondria contacts which affects TFEB nuclear translocation.Nature communications · 2024Article
- Novel strategies targeting mitochondria-lysosome contact sites for the treatment of neurological diseases.Frontiers in molecular neuroscience · 2024Review
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Authors and funding
8 authors at 5 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Mutations in the GDAP1 gene cause Charcot-Marie-Tooth (CMT) neuropathy. GDAP1 is an atypical glutathione S-transferase (GST) of the outer mitochondrial membrane and the mitochondrial membrane contacts with the endoplasmic reticulum (MAMs). Here, we investigate the role of this GST in the autophagic flux and the membrane contact sites (MCSs) between mitochondria and lysosomes in the cellular pathophysiology of GDAP1 deficiency. We demonstrate that GDAP1 participates in basal autophagy and that its depletion affects LC3 and PI3P biology in autophagosome biogenesis and membrane trafficking from MAMs. GDAP1 also contributes to the maturation of lysosome by interacting with PYKfyve kinase, a pH-dependent master lysosomal regulator. GDAP1 deficiency causes giant lysosomes with hydrolytic activity, a delay in the autophagic lysosome reformation, and TFEB activation. Notably, we found that GDAP1 interacts with LAMP-1, which supports that GDAP1-LAMP-1 is a new tethering pair of mitochondria and lysosome membrane contacts. We observed mitochondria-lysosome MCSs in soma and axons of cultured mouse embryonic motor neurons and human neuroblastoma cells. GDAP1 deficiency reduces the MCSs between these organelles, causes mitochondrial network abnormalities, and decreases levels of cellular glutathione (GSH). The supply of GSH-MEE suffices to rescue the lysosome membranes and the defects of the mitochondrial network, but not the interorganelle MCSs nor early autophagic events. Overall, we show that GDAP1 enables the proper function of mitochondrial MCSs in both degradative and nondegradative pathways, which could explain primary insults in GDAP1-related CMT pathophysiology, and highlights new redox-sensitive targets in axonopathies where mitochondria and lysosomes are involved.
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