Function of HTim8a in Complex IV Assembly in Neuronal Cells Provides Insight into Pathomechanism Underlying Mohr-Tranebjærg Syndrome

Overview

Journal Elife

Specialty Biology

Date 2019 Nov 5

PMID 31682224

Citations 21

Authors

Yilin Kang

Alexander J Anderson

Thomas Daniel Jackson

Catherine S Palmer

David P de Souza

Kenji M Fujihara

Tegan Stait

Ann E Frazier

Nicholas J Clemons

Deidreia Tull

David R Thorburn

Malcolm J McConville

Michael T Ryan

David A Stroud

Diana Stojanovski

Affiliations

Soon will be listed here.

Abstract

Human Tim8a and Tim8b are members of an intermembrane space chaperone network, known as the small TIM family. Mutations in 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.

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