TBC1D24 regulates mitochondria and endoplasmic reticulum-mitochondria contact sites

The RabGAP protein TBC1D24 is mutated in several neurological disorders including DOORS syndrome (Deafness, Onycho-Osteodystrophy, Mental Retardation, Seizures). Although TBC1D24 comprises two highly conserved domains -- the Tre2/Bub2/Cdc16 (TBC) domain and the TLDc domain -- both of which seem to play critical roles in cellular functions, its exact physiological function within the cell remains poorly understood. Here, we show that TBC1D24 affects mitochondrial structure and activity. Specifically, both primary fibroblasts from patients with TBC1D24 mutations and cells in which TBC1D24 has been knocked down exhibit fragmented mitochondria, decreased ATP production, and reduced mitochondrial membrane potential. Importantly, loss or mutation of TBC1D24 also alters sites of contact between the endoplasmic reticulum (ER) and mitochondria (ERMCS). These sites are vital for mitochondrial fusion and fission processes, which regulate mitochondrial dynamics and, consequently, mitochondrial activity. Altogether, our results uncover a new role for TBC1D24 in the regulation of mitochondrial functions and ERMCS which likely contribute to the neurological dysfunction present in affected patients.