Biallelic variants in TBC1-domain containing kinase (TBCK) cause intellectual disability in children. It remains unclear how variants in TBCK 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 TBCK 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 TBCK-/- 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 TBCK-/- 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.

中文翻译：

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溶酶体功能障碍损害线粒体质量控制，并预测TBCKE中的神经变性

含有TBC1结构域的激酶（TBCK）中的双等位基因变异会导致儿童智力残疾。尚不清楚TBCK的变异如何导致神经发育障碍以及哪些生物学因素调节临床严重性的变异性。先前的研究表明，共有截短的（p.R126X）Boricua纯合TBCK变体的患者自噬体增多，这些变体表现出严重的进行性神经退行性表型。由于线粒体的缺陷与神经退行性疾病有关，因此我们测试了线粒体和线粒体功能在TBCK //-成纤维细胞中是否改变。我们的数据显示线粒体大量积累，线粒体呼吸能力降低和mtDNA消耗。此外，线粒体功能障碍与神经表型的严重程度有关。由于有效的线粒体和线粒体的降解最终取决于成功的溶酶体降解，因此我们也测试了溶酶体功能。我们的数据表明，TBCK-/-成纤维细胞中的溶酶体蛋白水解功能显着降低。此外，酸化溶酶体纳米颗粒可以挽救线粒体呼吸系统的缺陷，这表明溶酶体功能障碍继发的线粒体质量控制受损，可能在这种罕见的神经发育障碍的致病性中发挥重要作用，并预测疾病进展和神经变性的程度。