TY - JOUR T1 - Neuronal-specific function of hTim8a in Complex IV assembly provides insight into the molecular mechanism underlying Mohr-Tranebjærg syndrome JF - bioRxiv DO - 10.1101/725655 SP - 725655 AU - Yilin Kang AU - Alexander J. Anderson AU - David P. De Souza AU - Catherine S. Palmer AU - Kenji M. Fujihara AU - Tegan Stait AU - Ann E Frazier AU - Nicholas J. Clemons AU - Dedreia Tull AU - David R Thorburn AU - Malcolm J. McConville AU - Michael T. Ryan AU - David A. Stroud AU - Diana Stojanovski Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/08/05/725655.abstract N2 - Human Tim8a is a member of an intermembrane space chaperone network, known as the small TIM family, which transport hydrophobic membrane proteins through this compartment. 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 and consequently how lack of hTim8a leads to a neurodegenerative disease. We identified a novel cell-specific function of hTim8a in the assembly of Complex IV, which is mediated through a transient interaction with the copper chaperone COX17. Complex IV assembly defects in cells lacking hTim8a leads to oxidative stress and changes to key apoptotic regulators, including cytochrome c and Bax, which primes cells for cell death. Alleviation of oxidative stress using Vitamin E rescues cells from apoptotic vulnerability. We hypothesis that enhanced sensitivity of neuronal cells to apoptosis is the underlying mechanism of MTS. ER -