AarF domain containing kinase 3 (ADCK3) mutant cells display signs of oxidative stress, defects in mitochondrial homeostasis and lysosomal accumulation

Jason K. Cullen, Nor Azian Abdul Murad, Abrey Yeo, Matthew McKenzie, Micheal Ward, Kok Leong Chong, Nicole L. Schieber, Robert G. Parton, Yi Chieh Lim, Ernst Wolvetang, Ghassan J. Maghzal, Roland Stocker, Martin F. Lavin

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Autosomal recessive ataxias are a clinically diverse group of syndromes that in some cases are caused by mutations in genes with roles in the DNA damage response, transcriptional regulation or mitochondrial function. One of these ataxias, known as Autosomal Recessive Cerebellar Ataxia Type-2 (ARCA-2, also known as SCAR9/COQ10D4; OMIM: #612016), arises due to mutations in the ADCK3 gene. The product of this gene (ADCK3) is an atypical kinase that is thought to play a regulatory role in coenzyme Q10 (CoQ10) biosynthesis. Although much work has been performed on the S. cerevisiae orthologue of ADCK3, the cellular and biochemical role of its mammalian counterpart, and why mutations in this gene lead to human disease is poorly understood. Here, we demonstrate that ADCK3 localises to mitochondrial cristae and is targeted to this organelle via the presence of an N-terminal localisation signal. Consistent with a role in CoQ10 biosynthesis, ADCK3 deficiency decreased cellular CoQ10 content. In addition, endogenous ADCK3 was found to associate in vitro with recombinant Coq3, Coq5, Coq7 and Coq9, components of the CoQ10 biosynthetic machinery. Furthermore, cell lines derived from ARCA-2 patients display signs of oxidative stress, defects in mitochondrial homeostasis and increases in lysosomal content. Together, these data shed light on the possible molecular role of ADCK3 and provide insight into the cellular pathways affected in ARCA-2 patients.

Original languageEnglish
Article numbere0148213
JournalPLoS One
Volume11
Issue number2
DOIs
Publication statusPublished - 1 Feb 2016

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coenzyme Q10
Oxidative stress
homeostasis
phosphotransferases (kinases)
Oxidative Stress
Homeostasis
oxidative stress
Phosphotransferases
mutants
Defects
Genes
cells
Biosynthesis
Ataxia
mutation
Mutation
genes
biosynthesis
Genetic Databases
human diseases

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

AarF domain containing kinase 3 (ADCK3) mutant cells display signs of oxidative stress, defects in mitochondrial homeostasis and lysosomal accumulation. / Cullen, Jason K.; Abdul Murad, Nor Azian; Yeo, Abrey; McKenzie, Matthew; Ward, Micheal; Chong, Kok Leong; Schieber, Nicole L.; Parton, Robert G.; Lim, Yi Chieh; Wolvetang, Ernst; Maghzal, Ghassan J.; Stocker, Roland; Lavin, Martin F.

In: PLoS One, Vol. 11, No. 2, e0148213, 01.02.2016.

Research output: Contribution to journalArticle

Cullen, JK, Abdul Murad, NA, Yeo, A, McKenzie, M, Ward, M, Chong, KL, Schieber, NL, Parton, RG, Lim, YC, Wolvetang, E, Maghzal, GJ, Stocker, R & Lavin, MF 2016, 'AarF domain containing kinase 3 (ADCK3) mutant cells display signs of oxidative stress, defects in mitochondrial homeostasis and lysosomal accumulation', PLoS One, vol. 11, no. 2, e0148213. https://doi.org/10.1371/journal.pone.0148213
Cullen, Jason K. ; Abdul Murad, Nor Azian ; Yeo, Abrey ; McKenzie, Matthew ; Ward, Micheal ; Chong, Kok Leong ; Schieber, Nicole L. ; Parton, Robert G. ; Lim, Yi Chieh ; Wolvetang, Ernst ; Maghzal, Ghassan J. ; Stocker, Roland ; Lavin, Martin F. / AarF domain containing kinase 3 (ADCK3) mutant cells display signs of oxidative stress, defects in mitochondrial homeostasis and lysosomal accumulation. In: PLoS One. 2016 ; Vol. 11, No. 2.
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