Function of hTim8a in complex IV assembly in neuronal cells provides insight into pathomechanism underlying Mohr-Tranebjærg syndrome
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
Yilin Kang
Department of Biochemistry and Molecular Biology, The University of Melbourne, Melbourne, Australia; The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, Australia
Alexander J Anderson
Department of Biochemistry and Molecular Biology, The University of Melbourne, Melbourne, Australia; The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, Australia
Thomas Daniel Jackson
Department of Biochemistry and Molecular Biology, The University of Melbourne, Melbourne, Australia; The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, Australia
Department of Biochemistry and Molecular Biology, The University of Melbourne, Melbourne, Australia; The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, Australia
David P De Souza
Metabolomics Australia, The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, Australia
Kenji M Fujihara
Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia
Tegan Stait
Murdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia
Ann E Frazier
Murdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia
Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia
Deidreia Tull
Metabolomics Australia, The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, Australia
David R Thorburn
Murdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia; Victorian Clinical Genetic Services, Royal Children's Hospital, Melbourne, Australia
Malcolm J McConville
Metabolomics Australia, The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, Australia
Michael T Ryan
Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Australia
David A Stroud
Department of Biochemistry and Molecular Biology, The University of Melbourne, Melbourne, Australia; The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, Australia
Department of Biochemistry and Molecular Biology, The University of Melbourne, Melbourne, Australia; The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, Australia
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, 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.
