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.
All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figure 1 (Table 1); Figure 2 (Table 2) and Figure 3 (Table 3. 4 and 5).
- Diana Stojanovski
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Agnieszka Chacinska, University of Warsaw, Poland
© 2019, Kang et al.
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