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Impaired cellular bioenergetics causes mitochondrial calcium handling defects in MT-ND5 mutant cybrids

McKenzie, Matthew and Duchen, Michael R. 2016, Impaired cellular bioenergetics causes mitochondrial calcium handling defects in MT-ND5 mutant cybrids, PLoS One, vol. 11, no. 4, pp. 1-12, doi: 10.1371/journal.pone.0154371.

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Title Impaired cellular bioenergetics causes mitochondrial calcium handling defects in MT-ND5 mutant cybrids
Formatted title Impaired cellular bioenergetics causes mitochondrial calcium handling defects in MT-ND5 mutant cybrids
Author(s) McKenzie, MatthewORCID iD for McKenzie, Matthew orcid.org/0000-0001-7508-1800
Duchen, Michael R.
Journal name PLoS One
Volume number 11
Issue number 4
Article ID e0154371
Start page 1
End page 12
Total pages 12
Publisher Public Library of Science
Place of publication San Francisco, Calif.
Publication date 2016-04-25
ISSN 1932-6203
Keyword(s) Adenosine Triphosphate
Calcium
Cell Line, Tumor
Deoxyglucose
Electron Transport Complex I
Fibroblasts
Gene Expression Regulation
Glycolysis
Humans
Hybrid Cells
MELAS Syndrome
Membrane Potential, Mitochondrial
Mitochondria
Mitochondrial Proteins
Mutation
NAD
Osteoblasts
Oxidative Phosphorylation
Primary Cell Culture
Signal Transduction
Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
OXIDATIVE-PHOSPHORYLATION
DNA MUTATIONS
CELLS
DEATH
ENCEPHALOMYOPATHY
HOMEOSTASIS
APOPTOSIS
NEURONS
MTDNA
GENE
Summary Mutations in mitochondrial DNA (mtDNA) can cause mitochondrial disease, a group of metabolic disorders that affect both children and adults. Interestingly, individual mtDNA mutations can cause very different clinical symptoms, however the factors that determine these phenotypes remain obscure. Defects in mitochondrial oxidative phosphorylation can disrupt cell signaling pathways, which may shape these disease phenotypes. In particular, mitochondria participate closely in cellular calcium signaling, with profound impact on cell function. Here, we examined the effects of a homoplasmic m.13565C>T mutation in MT-ND5 on cellular calcium handling using transmitochondrial cybrids (ND5 mutant cybrids). We found that the oxidation of NADH and mitochondrial membrane potential (Δψm) were significantly reduced in ND5 mutant cybrids. These metabolic defects were associated with a significant decrease in calcium uptake by ND5 mutant mitochondria in response to a calcium transient. Inhibition of glycolysis with 2-deoxy-D-glucose did not affect cytosolic calcium levels in control cybrids, but caused an increase in cytosolic calcium in ND5 mutant cybrids. This suggests that glycolytically-generated ATP is required not only to maintain Δψm in ND5 mutant mitochondria but is also critical for regulating cellular calcium homeostasis. We conclude that the m.13565C>T mutation in MT-ND5 causes defects in both mitochondrial oxidative metabolism and mitochondrial calcium sequestration. This disruption of mitochondrial calcium handling, which leads to defects in cellular calcium homeostasis, may be an important contributor to mitochondrial disease pathogenesis.
Language eng
DOI 10.1371/journal.pone.0154371
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, McKenzie, Duchen
Free to Read? Yes
Use Rights Creative Commons Attribution licence
Persistent URL http://hdl.handle.net/10536/DRO/DU:30111628

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.