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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.

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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, MatthewORCID iD for 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? Yes
Use Rights Creative Commons Attribution licence
Persistent URL http://hdl.handle.net/10536/DRO/DU:30111625

Document type: Journal Article
Collections: School of Life and Environmental Sciences
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Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.