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, Norazian, 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 and Lavin, Martin F. 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, pp. 1-28, doi: 10.1371/journal.pone.0148213. Attached Files Name Description MIMEType Size Downloads mckenzie-aarfdomain-2016.pdf Published version application/pdf 8.31MB 131 Title AarF domain containing kinase 3 (ADCK3) mutant cells display signs of oxidative stress, defects in mitochondrial homeostasis and lysosomal accumulation Author(s) Cullen, Jason K. Abdul Murad, Norazian Yeo, Abrey McKenzie, Matthew orcid.org/0000-0001-7508-1800 Ward, Micheal Chong, Kok Leong Schieber, Nicole L. Parton, Robert G. Lim, Yi Chieh Wolvetang, Ernst Maghzal, Ghassan J. Stocker, Roland Lavin, Martin F. Journal name PLoS One Volume number 11 Issue number 2 Article ID e0148213 Start page 1 End page 28 Total pages 28 Publisher Public Library of Science Place of publication San Francisco, Calif. Publication date 2016-02 ISSN 1932-6203 Keyword(s) Cell Survival Cytosol DNA Damage Endopeptidase K Gene Expression Regulation Glutathione Transferase HeLa Cells Homeostasis Humans Lentivirus Lysosomes Membrane Potential, Mitochondrial Mitochondria Mitochondrial Proteins Mutagenesis, Site-Directed Mutation Oxidative Phosphorylation Oxidative Stress Protein Structure, Tertiary RNA Interference Reactive Oxygen Species Recombinant Fusion Proteins Saccharomyces cerevisiae Saccharomyces cerevisiae Proteins Ubiquinone Science & Technology Multidisciplinary Sciences Science & Technology - Other Topics COENZYME Q(10) DEFICIENCY SACCHAROMYCES-CEREVISIAE UBIQUINONE BIOSYNTHESIS CAENORHABDITIS-ELEGANS COQ(10) DEFICIENCY CEREBELLAR-ATAXIA RAT-LIVER LIFE-SPAN COMPLEX MUTATIONS Summary 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. Language eng DOI 10.1371/journal.pone.0148213 Field of Research MD Multidisciplinary HERDC Research category C1.1 Refereed article in a scholarly journal ERA Research output type C Journal article Copyright notice ©2016, Cullen et al. Free to Read? 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