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: Mikhail Strokin, Georg Reiser
• Journal: Neurochemistry international (Neurochem Int) Vol. 99 Pg. 187-193 (10 2016) ISSN: 1872-9754 [Electronic] England
• PMID: 27395788 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016. Published by Elsevier Ltd.

Chemical References

• Group VI Phospholipases A2
• Pla2g6 protein, mouse

Topics

• Animals
• Calcium Signaling (physiology)
• Disease Models, Animal
• Group VI Phospholipases A2 (genetics, metabolism)
• Humans
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Mitochondria (genetics, metabolism)
• Neuroaxonal Dystrophies (genetics, metabolism)
• Rats
• Rats, Wistar