TY - JOUR TI - Function of hTim8a in complex IV assembly in neuronal cells provides insight into pathomechanism underlying Mohr-Tranebjærg syndrome AU - Kang, Yilin AU - Anderson, Alexander J AU - Jackson, Thomas Daniel AU - Palmer, Catherine S AU - De Souza, David P AU - Fujihara, Kenji M AU - Stait, Tegan AU - Frazier, Ann E AU - Clemons, Nicholas J AU - Tull, Deidreia AU - Thorburn, David R AU - McConville, Malcolm J AU - Ryan, Michael T AU - Stroud, David A AU - Stojanovski, Diana A2 - Chacinska, Agnieszka A2 - Malhotra, Vivek A2 - Herrmann, Johannes M VL - 8 PY - 2019 DA - 2019/11/04 SP - e48828 C1 - eLife 2019;8:e48828 DO - 10.7554/eLife.48828 UR - https://doi.org/10.7554/eLife.48828 AB - Human Tim8a and Tim8b are members of an intermembrane space chaperone network, known as the small TIM family. Mutations in TIMM8A cause a neurodegenerative disease, Mohr-Tranebjærg syndrome (MTS), which is characterised by sensorineural hearing loss, dystonia and blindness. Nothing is known about the function of hTim8a in neuronal cells or how mutation of this protein leads to a neurodegenerative disease. We show that hTim8a is required for the assembly of Complex IV in neurons, which is mediated through a transient interaction with Complex IV assembly factors, in particular the copper chaperone COX17. Complex IV assembly defects resulting from loss of hTim8a leads to oxidative stress and changes to key apoptotic regulators, including cytochrome c, which primes cells for death. Alleviation of oxidative stress with Vitamin E treatment rescues cells from apoptotic vulnerability. We hypothesise that enhanced sensitivity of neuronal cells to apoptosis is the underlying mechanism of MTS. KW - mitochondria KW - protein trafficking KW - Complex IV KW - chaperones KW - mitochondrial disease JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -