Function of hTim8a in complex IV assembly in neuronal cells provides insight into pathomechanism underlying Mohr-Tranebjærg syndrome
Open Access
- 4 November 2019
- journal article
- research article
- Published by eLife Sciences Publications, Ltd in eLife
Abstract
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 and Bax, which primes cells for death. Alleviation of oxidative stress by Vitamin E rescues cells from apoptotic vulnerability. We hypothesise that enhanced sensitivity of neuronal cells to apoptosis is the underlying mechanism of MTS.Keywords
Funding Information
- Australian Research Council (DP170101249)
- Melbourne International Fee Remission Scholarship
- Melbourne International Research Scholarship
- Mito Foundation (Research Fellowship)
- NHMRC
- NHMRC (Project Grant 1125390)
- NHMRC (Project Grant 1107094)
- NHMRC (Project Grant 1140906)
- NHMRC (Fellowship 1140851)
- NHMRC (Fellowship 1022896)
- NHMRC (Fellowship 1059530)
- Victorian Cancer Agency (MCRF16002)
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