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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/217059
Differential effects of Mendelian GDAP1 clinical variants on mitochondria-lysosome membrane contacts sites
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GDAP1 pathogenic variants cause Charcot-Marie-Tooth (CMT) disease, the most common hereditary motor and sensory neuropathy. CMT-GDAP1 can be axonal or demyelinating, with autosomal dominant or recessive inheritance, leading to phenotypic heterogeneity. Recessive GDAP1 variants cause a severe phenotype, whereas dominant variants are associated with a milder disease course. GDAP1 is an outer mitochondrial membrane protein involved in mitochondrial membrane contact sites (MCSs) with the plasmatic membrane, the endoplasmic reticulum (ER), and lysosomes. In GDAP1-deficient models, the pathophysiology includes morphological defects in mitochondrial network and ER, impaired Ca2+ homeostasis, oxidative stress, and mitochondrial MCSs defects. Nevertheless, the underlying pathophysiology of dominant variants is less understood.
Here, we study the effect upon mitochondria–lysosome MCSs of two GDAP1 clinical variants located in the α-loop interaction domain of the protein. p.Thr157Pro dominant variant causes the increase in these MCSs that correlates with a hyper-fissioned mitochondrial network. In contrast, p.Arg161His recessive variant, which is predicted to significantly change the contact surface of GDAP1, causes decreased contacts with more elongated mitochondria.
Given that mitochondria–lysosome MCSs regulate Ca2+ transfer from the lysosome to mitochondria, our results support that GDAP1 clinical variants have different consequences for Ca2+ handling and that could be primary insults determining differences in severity between dominant and recessive forms of the disease.
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CANTARERO, Lara, GARCÍA-VARGAS, Gisela, HOENICKA, Janet, PALAU MARTÍNEZ, Francesc. Differential effects of Mendelian GDAP1 clinical variants on mitochondria-lysosome membrane contacts sites. _Biology Open_. 2023. Vol. 12, núm. 4, pàgs. 1-9. [consulta: 29 de gener de 2026]. ISSN: 2046-6390. [Disponible a: https://hdl.handle.net/2445/217059]