To determine if mitochondrial dysfunction is associated with TBCK encephaloneuronopathy, a novel pediatric neurodegenerative syndrome.

We have shown that loss of TBCK leads  to increased autophagic flux in patient’s fibroblasts.  Since downregulation of mTORC1 is known to regulate oxidative phosphorylation, mitochondrial biogenesis, and mitophagy, we characterized mitochondrial function and quantified mitophagy in TBCKE patients' fibroblasts.

 Our data shows downregulation of mitochondrial biogenesis via PGC1-alpha, decreased mtDNA copy number, and upregulation of mitophagy in TBCK^-/- fibroblasts.  Furthermore, we show that mitochondrial respiration and mtDNA copy number correlates with the severity of the disease phenotype.

Our data suggests that loss-of-function mutations in TBCK presenting with a severe phenotype, specifically patients with the Boricua mutation, have aberrant mitophagy. Further studies are needed to address whether mitochondrial dysfunction contributes to the observed motor neuronopathy and neurodegenerative phenotype.