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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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Flies lacking iPLA2-VIA have increased lipid peroxidation in their brains and reduced triacylglycerol (TAG) levels. (A) Lipid peroxidation was measured using C11-BODIPY581/591 and demonstrated that Day 25 iPLA2-VIA−/− fly brains have elevated levels of lipid peroxidation compared with age-matched w1118 controls (n = 6 fly brains per experiment; **P < 0.01). (B) Whole-body triacylglycerol levels are decreased in iPLA2-VIA−/− flies in an age-dependent manner compared with w1118 control flies. (***P = 0.005 Day 20 and *P = 0.01 Day 32). (C) Day 15 iPLA2-VIA−/− flies are more sensitive to starvation conditions than age-matched w1118 control flies (P = 0.001; n = 150 flies per genotype).
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awv132-F5: Flies lacking iPLA2-VIA have increased lipid peroxidation in their brains and reduced triacylglycerol (TAG) levels. (A) Lipid peroxidation was measured using C11-BODIPY581/591 and demonstrated that Day 25 iPLA2-VIA−/− fly brains have elevated levels of lipid peroxidation compared with age-matched w1118 controls (n = 6 fly brains per experiment; **P < 0.01). (B) Whole-body triacylglycerol levels are decreased in iPLA2-VIA−/− flies in an age-dependent manner compared with w1118 control flies. (***P = 0.005 Day 20 and *P = 0.01 Day 32). (C) Day 15 iPLA2-VIA−/− flies are more sensitive to starvation conditions than age-matched w1118 control flies (P = 0.001; n = 150 flies per genotype).

Mentions: Despite the absence of changes in oxidized cardiolipin, we hypothesized that loss of PLA2G6 may lead to abnormal and excessive oxidation of other mitochondrial membrane lipids, which in turn would lead to the observed mitochondrial dysfunction. We therefore studied the effect of knocking out iPLA2-VIA on lipid peroxidation in Drosophila. Rates of lipid peroxidation were measured by live imaging of Day 25 iPLA2-VIA−/− and w1118 control dissected fly brains, using the fluorescent ratiometric oxidation-sensitive dye C11 BODIPY581/591, which shifts its fluorescence from red to green in a time-dependent manner, the rate being proportional to levels of lipid peroxidation. The changes in colour shift were detected by confocal microscopy. This demonstrated that levels of lipid peroxidation in flies lacking the iPLA2-VIA gene were 3.5-fold higher than in age-matched control fly brains (Fig. 5A).Figure 5


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)

Flies lacking iPLA2-VIA have increased lipid peroxidation in their brains and reduced triacylglycerol (TAG) levels. (A) Lipid peroxidation was measured using C11-BODIPY581/591 and demonstrated that Day 25 iPLA2-VIA−/− fly brains have elevated levels of lipid peroxidation compared with age-matched w1118 controls (n = 6 fly brains per experiment; **P < 0.01). (B) Whole-body triacylglycerol levels are decreased in iPLA2-VIA−/− flies in an age-dependent manner compared with w1118 control flies. (***P = 0.005 Day 20 and *P = 0.01 Day 32). (C) Day 15 iPLA2-VIA−/− flies are more sensitive to starvation conditions than age-matched w1118 control flies (P = 0.001; n = 150 flies per genotype).
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awv132-F5: Flies lacking iPLA2-VIA have increased lipid peroxidation in their brains and reduced triacylglycerol (TAG) levels. (A) Lipid peroxidation was measured using C11-BODIPY581/591 and demonstrated that Day 25 iPLA2-VIA−/− fly brains have elevated levels of lipid peroxidation compared with age-matched w1118 controls (n = 6 fly brains per experiment; **P < 0.01). (B) Whole-body triacylglycerol levels are decreased in iPLA2-VIA−/− flies in an age-dependent manner compared with w1118 control flies. (***P = 0.005 Day 20 and *P = 0.01 Day 32). (C) Day 15 iPLA2-VIA−/− flies are more sensitive to starvation conditions than age-matched w1118 control flies (P = 0.001; n = 150 flies per genotype).
Mentions: Despite the absence of changes in oxidized cardiolipin, we hypothesized that loss of PLA2G6 may lead to abnormal and excessive oxidation of other mitochondrial membrane lipids, which in turn would lead to the observed mitochondrial dysfunction. We therefore studied the effect of knocking out iPLA2-VIA on lipid peroxidation in Drosophila. Rates of lipid peroxidation were measured by live imaging of Day 25 iPLA2-VIA−/− and w1118 control dissected fly brains, using the fluorescent ratiometric oxidation-sensitive dye C11 BODIPY581/591, which shifts its fluorescence from red to green in a time-dependent manner, the rate being proportional to levels of lipid peroxidation. The changes in colour shift were detected by confocal microscopy. This demonstrated that levels of lipid peroxidation in flies lacking the iPLA2-VIA gene were 3.5-fold higher than in age-matched control fly brains (Fig. 5A).Figure 5

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