title: Mitochondria from a mouse model of the human infantile neuroaxonal dystrophy (INAD) with genetic defects in VIA iPLA2 have disturbed Ca(2+) regulation with reduction in Ca(2+) capacity.
abstract: Mutations in the PLA2G6 gene which encodes Ca(2+)-independent phospholipase A2 (VIA iPLA2) were detected in 85% of cases of the inherited degenerative nervous system disorder INAD (infantile neuroaxonal dystrophy, OMIM #256600). However, molecular mechanisms linking these mutations to the disease progression are unclear. VIA iPLA2 is expressed also in mitochondria. Here, we investigate Ca(2+) handling by brain mitochondria derived from mice with hypomorph Pla2g6 allele. These animals with reduced transcript levels (5% of wild type) represent a suitable model for INAD. We demonstrated significant reduction of Ca(2+) uptake rate and Ca(2+) retention capacity in brain mitochondria isolated from this mutant. This phenotype could be mimicked when in wild-type controls VIA iPLA2 was inhibited by S-BEL. Importantly, the reduction could be ameliorated partly by addition of the VIA iPLA2 product, sn-2 lysophosphatidyl-choline. Furthermore, we demonstrated in situ a reduced mitochondrial potential in neurons from mice deficient in VIA iPLA2, which could cause the reduced Ca(2+) uptake rate via the potential-dependent mitochondrial Ca(2+) uniporter. Thus, the disturbances in mitochondrial potential and the changes in Ca(2+) handling were dependent on VIA iPLA2 activity. Reduced mitochondrial Ca(2+) uptake rate and Ca(2+) retention capacity might result in increased vulnerability of mitochondria to the Ca(2+) overload and in disturbed cellular Ca(2+) signaling during INAD. For VIA iPLA2, non-canonical functions beyond sole phospholipid turnover seem to be important, such as regulation of store-operated Ca(2+) entry in cells. Thus, our findings bring new insight into molecular mechanism affected in INAD and highlight the non-canonical function of VIA iPLA2 in regulation of mitochondrial Ca(2+) handling.
authors.affiliation: Medizinische Fakultät der Otto-von-Guericke-Universität Magdeburg, Institut für Neurobiochemie (Institut für Inflammation und Neurodegeneration), Magdeburg, Germany.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Strokin
authors.affiliation: Medizinische Fakultät der Otto-von-Guericke-Universität Magdeburg, Institut für Neurobiochemie (Institut für Inflammation und Neurodegeneration), Magdeburg, Germany. Electronic address: georg.reiser@med.ovgu.de.
authors.forename: Georg
authors.initials: G
authors.lastname: Reiser
mesh_terms: D000818:Animals; D020013:Calcium Signaling / Q000502:physiology*; D004195:Disease Models, Animal; D054522:Group VI Phospholipases A2 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D019150:Neuroaxonal Dystrophies / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D054522:Group VI Phospholipases A2; C516476:Pla2g6 protein, mouse
keywords: Ca(2+) signaling; Infantile neuroaxonal dystrophy (INAD); Mitochondrial disorder; Mouse models of INAD; Neuron; Phospholipase A(2)