• 1 QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
  • 2 Hudson Institute of Medical Research, Centre for Genetic Diseases, Melbourne, VIC, Australia
  • 3 Mater Medical Research Institute, Glycation and Diabetic Complications Group, Translational Research Institute, Brisbane, QLD, Australia
  • 4 Queensland University of Technology, ARC Centre of Excellence for Free Radical Chemistry and Biotechnology, Brisbane, QLD, Australia
  • 5 The University of Queensland, Institute for Molecular Bioscience and Centre for Microscopy and Microanalysis, St. Lucia, QLD, Australia
  • 6 The University of Queensland, Australian Institute for Bioengineering and Nanotechnology, Brisbane, Australia
  • 7 Victor Chang Cardiac Research Institute, Vascular Biology Division, Darlinghurst, Australia
  • 8 The University of Queensland Centre for Clinical Research, Brisbane, QLD, Australia
PLoS One, 2016;11(2):e0148213.
PMID: 26866375 DOI: 10.1371/journal.pone.0148213


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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.