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2023-04-03

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cc-by (c) Cantarero Lara et al., 2023
Please use this identifier to cite or link to this item: https://hdl.handle.net/2445/217059

Differential effects of Mendelian GDAP1 clinical variants on mitochondria-lysosome membrane contacts sites

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https://doi.org/10.1242/bio.059707

Abstract

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.

Subject

Lisosomes, Amiotròfia neural progressiva de Charcot-Marie-Tooth, Proteïnes de membrana, Mitocondris

Subject (English)

Lysosomes, Charcot-Marie-Tooth disease, Membrane proteins, Mitochondria

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Articles publicats en revistes (Cirurgia i Especialitats Medicoquirúrgiques)

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CANTARERO, Lara, et al. Differential effects of Mendelian GDAP1 clinical variants on mitochondria-lysosome membrane contacts sites. Biology Open. 2023. Vol. 12, num. 4, pags. 1-9. ISSN 2046-6390. [consulted: 19 of August of 2026]. Available at: https://hdl.handle.net/2445/217059

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