Abstract
Patatin-like phospholipase domain-containing protein PNPLA8, also termed Ca2+-independent phospholipase A2γ (iPLA2γ), is addressed to the mitochondrial matrix (or peroxisomes), where it may manifest its unique activity to cleave phospholipid side-chains from both sn-1 and sn-2 positions, consequently releasing either saturated or unsaturated fatty acids (FAs), including oxidized FAs. Moreover, iPLA2γ is directly stimulated by H2O2 and, hence, is activated by redox signaling or oxidative stress. This redox activation permits the antioxidant synergy with mitochondrial uncoupling proteins (UCPs) or other SLC25 mitochondrial carrier family members by FA-mediated protonophoretic activity, termed mild uncoupling, that leads to diminishing of mitochondrial superoxide formation. This mechanism allows for the maintenance of the steady-state redox status of the cell. Besides the antioxidant role, we review the relations of iPLA2γ to lipid peroxidation since iPLA2γ is alternatively activated by cardiolipin hydroperoxides and hypothetically by structural alterations of lipid bilayer due to lipid peroxidation. Other iPLA2γ roles include the remodeling of mitochondrial (or peroxisomal) membranes and the generation of specific lipid second messengers. Thus, for example, during FA β-oxidation in pancreatic β-cells, H2O2-activated iPLA2γ supplies the GPR40 metabotropic FA receptor to amplify FA-stimulated insulin secretion. Cytoprotective roles of iPLA2γ in the heart and brain are also discussed.
Highlights
We found that both challenges increase the acute oxidative stress in the lung and spleen, suggesting that the antioxidant synergy of UCP2 and independent phospholipase A2γ (iPLA2γ) belongs to significant cytoprotective and anti-inflammatory mechanisms in these tissues
We focused on clarifying the molecular mechanism of antioxidant synergy involving phospholipase iPLA2γ and selected fatty acid–translocating mitochondrial SLC25 family proteins
The unique ability of iPLA2γ to cleave phospholipid acyl chains from both sn-1 and sn-2 positions allows for various ways of the spatiotemporal release of saturated andunsaturated fatty acids of diverse properties
Summary
(PLA2) enzymes were identified and subdivided into several classes. Overview of selected phospholipases with the focus on group VI intracellular calcium-independent phospholipases A2 is shown in Table 1, below. The only Group VI PLA2 enzyme known to contain the N-terminal mitochondrial localization sequence (besides the peroxisomal one) is PNPLA8, termed iPLA2γ [14,26] Another widely studied PLA2 isoform PNPLA9/iPLA2β was reported to act in mitochondria [27] and to participate in mitochondrial membrane repair following lipid peroxidation [28]. Independence of the enzyme activity could theoretically be considered as that the enzyme is active when it encounters specific structural alterations in the lipid bilayer Such alterations can be caused by PUFAs, cardiolipin, and even hydroxy or peroxy groups existing in phospholipid FA side-chains and usually localized at the water/lipid interface. It was shown that high-fat diet activates liver iPLA2γ generating eicosanoids ( 12-HETE), leading to mitochondrial dysfunction and hepatic cell death [46]
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