Neuronal-specific function of hTim8a in Complex IV assembly provides insight into the molecular mechanism underlying Mohr-Tranebjærg syndrome

Abstract

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-Tranebjaerg 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. Rabbit polyclonal NDUFAF2 N/A Mike Ryan, Monash UniversityRabbit polyclonal hTom40 N/A

Functional analysis of a novel mutation in the TIMM8A gene that causes deafness‐dystonia‐optic neuronopathy syndrome

“…This and other studies show that loss of TIMM8A results in abnormal mitochondrial morphology but this is not associated with any obvious impact on mitochondrial energetics (Binder et al, ; Engl et al, ). More recently, loss of Tim8a in neurons was shown to cause defects in Complex IV assembly, priming these cells for apoptotic vulnerability (Kang et al, ). Most of the mutations associated with DDON syndrome are frameshifts or premature stops, and there are a few missense mutations reported, including two in the first codon of the gene (Aguirre et al, ; Binder et al, ; Blesa et al, ; Hofmann et al, ; Penamora‐Destriza et al, ; Ujike, Tanabe, Takehisa, Hayabara, & Kuroda, ; Wang et al, ).…”