The PLA2G6 gene encodes a group VIA calcium-independent phospholipase A2 beta 
enzyme that selectively hydrolyses glycerophospholipids to release free fatty 
acids. Mutations in PLA2G6 have been associated with disorders such as infantile 
neuroaxonal dystrophy, neurodegeneration with brain iron accumulation type II 
and Karak syndrome. More recently, PLA2G6 was identified as the causative gene 
in a subgroup of patients with autosomal recessive early-onset 
dystonia-parkinsonism. Neuropathological examination revealed widespread Lewy 
body pathology and the accumulation of hyperphosphorylated tau, supporting a 
link between PLA2G6 mutations and parkinsonian disorders. Here we show that 
knockout of the Drosophila homologue of the PLA2G6 gene, iPLA2-VIA, results in 
reduced survival, locomotor deficits and organismal hypersensitivity to 
oxidative stress. 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. We confirmed our findings using cultured 
fibroblasts taken from two patients with mutations in the PLA2G6 gene. 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. Finally, we demonstrated that deuterated 
polyunsaturated fatty acids, which inhibit lipid peroxidation, were able to 
partially rescue the locomotor abnormalities seen in aged flies lacking 
iPLA2-VIA gene function, and restore mitochondrial membrane potential in 
fibroblasts from patients with PLA2G6 mutations. Taken together, our findings 
demonstrate that loss of normal PLA2G6 gene activity leads to lipid 
peroxidation, mitochondrial dysfunction and subsequent mitochondrial membrane 
abnormalities. Furthermore we show that the iPLA2-VIA knockout fly model 
provides a useful platform for the further study of PLA2G6-associated 
neurodegeneration.