Differential effects of Mendelian GDAP1 clinical variants on mitochondria-lysosome membrane contacts sites.
Lara CantareroGisela García-VargasJanet HoenickaFrancesc PalauPublished in: Biology open (2023)
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.
Keyphrases
- endoplasmic reticulum
- oxidative stress
- copy number
- mitochondrial dna
- cell death
- intellectual disability
- fluorescent probe
- reactive oxygen species
- ischemia reperfusion injury
- muscular dystrophy
- living cells
- genome wide
- early onset
- estrogen receptor
- computed tomography
- binding protein
- protein protein
- heat shock
- optic nerve
- drug induced
- amino acid