{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T20:24:36Z","timestamp":1792009476080,"version":"4.4.0"},"reference-count":55,"publisher":"Oxford University Press (OUP)","issue":"22","license":[{"start":{"date-parts":[[2020,11,6]],"date-time":"2020-11-06T00:00:00Z","timestamp":1604620800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["ACCI 2019-16"],"award-info":[{"award-number":["ACCI 2019-16"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002809","name":"Generalitat de Catalunya","doi-asserted-by":"publisher","award":["2017\/SRG1308"],"award-info":[{"award-number":["2017\/SRG1308"]}],"id":[{"id":"10.13039\/501100002809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002809","name":"Generalitat de Catalunya","doi-asserted-by":"publisher","award":["2015 FEDER\/S-21"],"award-info":[{"award-number":["2015 FEDER\/S-21"]}],"id":[{"id":"10.13039\/501100002809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Spanish Ministry of Science, Innovation and Universities","award":["SAF2015-66625-R"],"award-info":[{"award-number":["SAF2015-66625-R"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,1,21]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Mutations in the GDAP1 gene cause Charcot\u2013Marie\u2013Tooth (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\u2013LAMP-1 is a new tethering pair of mitochondria and lysosome membrane contacts. We observed mitochondria\u2013lysosome 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<\/jats:p><jats:p>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.<\/jats:p>","DOI":"10.1093\/hmg\/ddaa243","type":"journal-article","created":{"date-parts":[[2020,11,3]],"date-time":"2020-11-03T12:09:22Z","timestamp":1604405362000},"page":"3589-3605","source":"Crossref","is-referenced-by-count":66,"title":["Mitochondria\u2013lysosome membrane contacts are defective in GDAP1-related Charcot\u2013Marie\u2013Tooth disease"],"prefix":"10.1093","volume":"29","author":[{"given":"Lara","family":"Cantarero","sequence":"first","affiliation":[{"name":"Department of Neurogenetics and Molecular Medicine\u2014IPER, Institut de Recerca Sant Joan de D\u00e9u (IRSJD), Barcelona 08950, Spain"},{"name":"Department of Neurogenetics and Molecular Medicine, Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER), Barcelona 08950, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Ju\u00e1rez-Escoto","sequence":"additional","affiliation":[{"name":"Department of Neurogenetics and Molecular Medicine\u2014IPER, Institut de Recerca Sant Joan de D\u00e9u (IRSJD), Barcelona 08950, Spain"},{"name":"Department of Neurogenetics and Molecular Medicine, Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER), Barcelona 08950, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Azahara","family":"Civera-Treg\u00f3n","sequence":"additional","affiliation":[{"name":"Department of Neurogenetics and Molecular Medicine\u2014IPER, Institut de Recerca Sant Joan de D\u00e9u (IRSJD), Barcelona 08950, Spain"},{"name":"Department of Neurogenetics and Molecular Medicine, Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER), Barcelona 08950, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"Rodr\u00edguez-Sanz","sequence":"additional","affiliation":[{"name":"Department of Neurogenetics and Molecular Medicine\u2014IPER, Institut de Recerca Sant Joan de D\u00e9u (IRSJD), Barcelona 08950, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00f3nica","family":"Rold\u00e1n","sequence":"additional","affiliation":[{"name":"Confocal Microscopy Unit, IPER, Department of Genetic and Molecular Medicine, and Department of Pathology, Hospital Sant Joan de D\u00e9u, Barcelona 08950, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ra\u00fal","family":"Ben\u00edtez","sequence":"additional","affiliation":[{"name":"Biomedical Engineering Research Center (CREB), Institut de Recerca Sant Joan de D\u00e9u (IRSJD), Barcelona 08950, Spain"},{"name":"Automatic Control Department and Biomedical Engineering Research Center, Universitat Polit\u00e8cnica de Catalunya, Barcelona 08028, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janet","family":"Hoenicka","sequence":"additional","affiliation":[{"name":"Department of Neurogenetics and Molecular Medicine\u2014IPER, Institut de Recerca Sant Joan de D\u00e9u (IRSJD), Barcelona 08950, Spain"},{"name":"Department of Neurogenetics and Molecular Medicine, Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER), Barcelona 08950, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesc","family":"Palau","sequence":"additional","affiliation":[{"name":"Department of Neurogenetics and Molecular Medicine\u2014IPER, Institut de Recerca Sant Joan de D\u00e9u (IRSJD), Barcelona 08950, Spain"},{"name":"Department of Neurogenetics and Molecular Medicine, Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER), Barcelona 08950, Spain"},{"name":"Department of Genetic and Molecular Medicine\u2014IPER, Hospital Sant Joan de D\u00e9u, Barcelona 08950, Spain"},{"name":"Department of General Internal Medicine, Clinic Institute of Medicine and Dermatology (ICMiD), Hospital Cl\u00ednic, Barcelona 08036, Spain"},{"name":"Division of Pediatrics, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona 08036, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,11,6]]},"reference":[{"key":"2021012301195150000_ref1","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1097\/WCO.0000000000000373","article-title":"Recent advances in the genetic neuropathies","volume":"29","author":"Rossor","year":"2016","journal-title":"Curr. 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