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Loss of PLA2G6 leads to elevated mitochondrial lipid peroxidation and mitochondrial dysfunction.

Kinghorn KJ, Castillo-Quan JI, Bartolome F, Angelova PR, Li L, Pope S, Cochemé HM, Khan S, Asghari S, Bhatia KP, Hardy J, Abramov AY, Partridge L - Brain (2015)

Bottom Line: Furthermore, we demonstrate that loss of iPLA2-VIA function leads to a number of mitochondrial abnormalities, including mitochondrial respiratory chain dysfunction, reduced ATP synthesis and abnormal mitochondrial morphology.Moreover, we show that loss of iPLA2-VIA is strongly associated with increased lipid peroxidation levels.Similar abnormalities were seen including elevated mitochondrial lipid peroxidation and mitochondrial membrane defects, as well as raised levels of cytoplasmic and mitochondrial reactive oxygen species.

View Article: PubMed Central - PubMed

Affiliation: 1 Institute of Healthy Ageing and Department of Genetics, Evolution and Environment, University College London, London WC1E 6BT, UK 2 Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK k.kinghorn@ucl.ac.uk.

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Human mutant PLA2G6 fibroblasts have reduced mitochondrial membrane potential and increased levels of mitochondrial and cytosolic reactive oxygen species levels. (A) The mitochondrial membrane potential of human p.R747W mutant PLA2G6 fibroblasts is reduced compared with control human fibroblasts (*P < 0.05 control 1 and **P < 0.002 control 2) as measured by TMRM fluorescence. (B) This is clearly seen as a reduction in red TMRM staining in the p.R747W mutant PLA2G6 human fibroblasts compared with control fibroblasts (Scale bars = 44 μm). (C) Mitochondrial reactive oxygen species production is increased 28% in human p.R747W mutant PLA2G6 fibroblasts compared to control fibroblasts (P < 0.001; n = 6). (D) Cytosolic reactive oxygen species production is also increased in human p.R747W mutant PLA2G6 fibroblasts compared with control fibroblasts (1.47-fold increase; P < 0.001; n = 6). (E) Rates of reactive oxygen species production in C and D are shown as a percentage. Het = dihydroethidium.
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awv132-F6: Human mutant PLA2G6 fibroblasts have reduced mitochondrial membrane potential and increased levels of mitochondrial and cytosolic reactive oxygen species levels. (A) The mitochondrial membrane potential of human p.R747W mutant PLA2G6 fibroblasts is reduced compared with control human fibroblasts (*P < 0.05 control 1 and **P < 0.002 control 2) as measured by TMRM fluorescence. (B) This is clearly seen as a reduction in red TMRM staining in the p.R747W mutant PLA2G6 human fibroblasts compared with control fibroblasts (Scale bars = 44 μm). (C) Mitochondrial reactive oxygen species production is increased 28% in human p.R747W mutant PLA2G6 fibroblasts compared to control fibroblasts (P < 0.001; n = 6). (D) Cytosolic reactive oxygen species production is also increased in human p.R747W mutant PLA2G6 fibroblasts compared with control fibroblasts (1.47-fold increase; P < 0.001; n = 6). (E) Rates of reactive oxygen species production in C and D are shown as a percentage. Het = dihydroethidium.

Mentions: Given that loss of iPLA2-VIA led to increased lipid peroxidation and mitochondrial dysfunction in Drosophila, we examined fibroblasts taken from a patient with a known homozygous p.R747W mutation in PLA2G6 causing dystonia-parkinsonism (Paisan-Ruiz et al., 2009). Using TMRM fluorescence to probe for mitochondrial membrane potential, we found that there was a significant decrease in basal mitochondrial membrane potential in the mutant human fibroblasts (Fig. 6A and B), similar to that seen in fly brains lacking iPLA2-VIA.Figure 6


Loss of PLA2G6 leads to elevated mitochondrial lipid peroxidation and mitochondrial dysfunction.

Kinghorn KJ, Castillo-Quan JI, Bartolome F, Angelova PR, Li L, Pope S, Cochemé HM, Khan S, Asghari S, Bhatia KP, Hardy J, Abramov AY, Partridge L - Brain (2015)

Human mutant PLA2G6 fibroblasts have reduced mitochondrial membrane potential and increased levels of mitochondrial and cytosolic reactive oxygen species levels. (A) The mitochondrial membrane potential of human p.R747W mutant PLA2G6 fibroblasts is reduced compared with control human fibroblasts (*P < 0.05 control 1 and **P < 0.002 control 2) as measured by TMRM fluorescence. (B) This is clearly seen as a reduction in red TMRM staining in the p.R747W mutant PLA2G6 human fibroblasts compared with control fibroblasts (Scale bars = 44 μm). (C) Mitochondrial reactive oxygen species production is increased 28% in human p.R747W mutant PLA2G6 fibroblasts compared to control fibroblasts (P < 0.001; n = 6). (D) Cytosolic reactive oxygen species production is also increased in human p.R747W mutant PLA2G6 fibroblasts compared with control fibroblasts (1.47-fold increase; P < 0.001; n = 6). (E) Rates of reactive oxygen species production in C and D are shown as a percentage. Het = dihydroethidium.
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awv132-F6: Human mutant PLA2G6 fibroblasts have reduced mitochondrial membrane potential and increased levels of mitochondrial and cytosolic reactive oxygen species levels. (A) The mitochondrial membrane potential of human p.R747W mutant PLA2G6 fibroblasts is reduced compared with control human fibroblasts (*P < 0.05 control 1 and **P < 0.002 control 2) as measured by TMRM fluorescence. (B) This is clearly seen as a reduction in red TMRM staining in the p.R747W mutant PLA2G6 human fibroblasts compared with control fibroblasts (Scale bars = 44 μm). (C) Mitochondrial reactive oxygen species production is increased 28% in human p.R747W mutant PLA2G6 fibroblasts compared to control fibroblasts (P < 0.001; n = 6). (D) Cytosolic reactive oxygen species production is also increased in human p.R747W mutant PLA2G6 fibroblasts compared with control fibroblasts (1.47-fold increase; P < 0.001; n = 6). (E) Rates of reactive oxygen species production in C and D are shown as a percentage. Het = dihydroethidium.
Mentions: Given that loss of iPLA2-VIA led to increased lipid peroxidation and mitochondrial dysfunction in Drosophila, we examined fibroblasts taken from a patient with a known homozygous p.R747W mutation in PLA2G6 causing dystonia-parkinsonism (Paisan-Ruiz et al., 2009). Using TMRM fluorescence to probe for mitochondrial membrane potential, we found that there was a significant decrease in basal mitochondrial membrane potential in the mutant human fibroblasts (Fig. 6A and B), similar to that seen in fly brains lacking iPLA2-VIA.Figure 6

Bottom Line: Furthermore, we demonstrate that loss of iPLA2-VIA function leads to a number of mitochondrial abnormalities, including mitochondrial respiratory chain dysfunction, reduced ATP synthesis and abnormal mitochondrial morphology.Moreover, we show that loss of iPLA2-VIA is strongly associated with increased lipid peroxidation levels.Similar abnormalities were seen including elevated mitochondrial lipid peroxidation and mitochondrial membrane defects, as well as raised levels of cytoplasmic and mitochondrial reactive oxygen species.

View Article: PubMed Central - PubMed

Affiliation: 1 Institute of Healthy Ageing and Department of Genetics, Evolution and Environment, University College London, London WC1E 6BT, UK 2 Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK k.kinghorn@ucl.ac.uk.

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Related in: MedlinePlus