Lysosomal dysfunction impairs mitochondrial quality control and predicts neurodegeneration in TBCKE

Biallelic variants in TBC1-domain containing kinase () cause intellectual disability in children. It remains unclear how variants in lead to a neurodevelopmental disorder and what biological factors modulate the variability of clinical severity. Previous studies showed increased autophagosomes in patients sharing the truncating (p.R126X) Boricua homozygous variant, who exhibit a severe and progressive neurodegenerative phenotype. Since defects in mitophagy are linked to neurodegenerative disorders, we tested whether mitophagy and mitochondrial function are altered in fibroblasts. Our data shows significant accumulation of mitophagosomes, reduced mitochondrial respiratory capacity, and mtDNA depletion. Furthermore, mitochondrial dysfunction correlates with the severity of the neurological phenotype. Since effective mitophagy and degradation of mitophagosomes ultimately depends on successful lysosomal degradation, we also tested lysosomal function. Our data shows that lysosomal proteolytic function is significantly reduced in fibroblasts. Moreover, acidifying lysosomal nanoparticles rescue the mitochondrial respiratory defects, suggesting that impaired mitochondrial quality control secondary to lysosomal dysfunction, may play an important role in the pathogenicity of this rare neurodevelopmental disorder and predict the degree of disease progression and neurodegeneration.