Jabůrek Martin, Průchová Pavla, Holendová Blanka, Galkin Alexander, Ježek Petr
Department of Mitochondrial Physiology, Institute of Physiology of the Czech Academy of Sciences, Vídeňská 1084, 14220 Prague, Czech Republic.
Department of Pediatrics, Division of Neonatology, Columbia University William Black Building, New York, NY 10032, USA.
Antioxidants (Basel). 2021 Apr 26;10(5):678. doi: 10.3390/antiox10050678.
Patatin-like phospholipase domain-containing protein PNPLA8, also termed Ca-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 HO 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, HO-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.
含帕他汀样磷脂酶结构域蛋白PNPLA8，也称为钙非依赖性磷脂酶A2γ（iPLA2γ），定位于线粒体基质（或过氧化物酶体），在那里它可能表现出独特的活性，从sn-1和sn-2位置切割磷脂侧链，从而释放饱和或不饱和脂肪酸（FAs），包括氧化脂肪酸。此外，iPLA2γ直接受血红素加氧酶（HO）刺激，因此受氧化还原信号或氧化应激激活。这种氧化还原激活通过FA介导的质子载体活性，即所谓的轻度解偶联，允许与线粒体解偶联蛋白（UCPs）或其他SLC25线粒体载体家族成员产生抗氧化协同作用，从而减少线粒体超氧化物的形成。这种机制有助于维持细胞的稳态氧化还原状态。除了抗氧化作用外，并考虑到iPLA2γ可被心磷脂氢过氧化物激活，也可能因脂质过氧化导致的脂质双层结构改变而被激活，我们还综述了iPLA2γ与脂质过氧化的关系。iPLA2γ的其他作用包括线粒体（或过氧化物酶体）膜的重塑以及特定脂质第二信使的产生。因此，例如，在胰腺β细胞的FAβ氧化过程中，HO激活的iPLA2γ为GPR40代谢型FA受体提供底物，以放大FA刺激的胰岛素分泌。我们还讨论了iPLA2γ在心脏和大脑中的细胞保护作用。
