Calcium-independent phospholipase A2γ (iPLA2γ) and its roles in cellular functions and diseases

Hara, Shuntaro; Yoda, Emiko; Sasaki, Yuka; Nakatani, Yoshihito; Kuwata, Hiroshi

doi:10.1016/j.bbalip.2018.10.009

Cited by 34 publications

(34 citation statements)

References 56 publications

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“…PNPLA8 is a calcium-independent phospholipases A2 (iPLA2s) belonging to a patatin-like protein family and shares homology with patatin, a lipid hydrolase. Having mitochondrial and peroxisomal localization signals in the N-terminal and C-terminal, respectively, it is the predominant phospholipase active in the mammalian mitochondria and peroxisome and is thought to have a role in maintaining lipid homeostasis in these organelles [Hara et al, 2019]. Presently, 9 PNPLA genes (PNPLA1-PNPLA9) are known in humans [Kienesberger et al, 2009].…”

Section: Discussionmentioning

confidence: 99%

Homozygous Missense Variation in PNPLA8 Causes Prenatal-Onset Severe Neurodegeneration

Masih

Moirangthem

Phadke³

2021

Mol Syndromol

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The patatin-like protein family plays an important role in various biological functions including lipid homeostasis, cellular growth, and signaling. Conserved across species, the patatin domain is shared by all 9 members of the PNPLA family without redundancy in the coding sequences. The defective function of PNPLA2, PNPLA6, and PNPLA9 are known to cause mitochondrial-related neurodegeneration. Recently, PNPLA8 has been associated with mitochondrial myopathy and poor weight gain with lactic acidosis in 3 unrelated families. Using whole-exome sequencing, we identified a homozygous novel missense variation c.1874A>G in the patatin domain of PNPLA8. The patient had prenatal-onset severe and progressive neurodegeneration with mortality in infancy.

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Section: Discussionmentioning

confidence: 99%

Homozygous Missense Variation in PNPLA8 Causes Prenatal-Onset Severe Neurodegeneration

Masih

Moirangthem

Phadke³

2021

Mol Syndromol

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“…(E)-6-(bromomethylene)-3-(1-naphthalenyl)-2H-tetrahydropyran-2-one, also termed R -bromoenol lactone ( R -BEL), is a highly selective inhibitor of iPLA2γ, whereas the S -enantiomer ( S -BEL) is ineffective, but is highly selective for iPLA2β [ 37 ]. The maintenance of lipid homeostasis of mitochondria and peroxisomes is consensually considered as a general function of iPLA2γ [ 16 ].…”

Section: Phospholipase A2 Group VI Patatin-like Phospholipase Domain-containing Proteins (Pnplas)mentioning

confidence: 99%

“…It has also been recognized that the IMM lipids or an inner phospholipid leaflet of the outer mitochondrial membrane (OMM) are targets of phospholipases A2 [ 14 , 15 , 16 ]. Unidentified mitochondrial isoforms studied in the past were eventually recognized as phospholipase A2 isoforms PNPLA8/iPLA2γ and probably also PNPLA9/iPLA2β (see below).…”

Section: Introductionmentioning

confidence: 99%

Antioxidant Synergy of Mitochondrial Phospholipase PNPLA8/iPLA2γ with Fatty Acid–Conducting SLC25 Gene Family Transporters

et al. 2021

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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.

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“…184 In contrast, oxygenated phospholipids serve as a source of lipid mediators and can be hydrolyzed by specialized phospholipases A 2 such as lipoprotein lipase A 2 or PAF hydrolase and calcium independent iPLA 2 γ or iPLA 2 β that catalytically hydrolyze preferentially oxygenated fatty acid residues. 25,185 High levels of expression of iPLA 2 γ , mainly localized in mitochondria, 186 is commonly associated with the accumulation of pro-inflammatory oxygenated octadecanoids and eicosanoids caused by the dysregulation of mitochondrial Ca 2+ mechanisms. 187,188 These mechanisms may be particularly important in mitochondria where hydrolysis of CLox by iPLA 2 γ , 93 yields a diversified series of pro-inflammatory and pro-resolving lipids mediators.…”

Section: Hydrolysis/re-esterification Of Oxigenated Lipids and Their mentioning

confidence: 99%

“…93 In addition, CL is exclusively localized in mitochondria and the subcellular localization of iPLA 2 γ is limited to mitochondrial membranes. 186 Furthermore, we recently demonstrated that the oxidation of polyunsaturated CLs in mitochondria and the accumulation of their hydrolysis products including oxygenated arachidonic acids are activated in vivo after acute tissue injury. 28 Thus, we suggested that CL and oxCL may be involved in the inflammatory response induced by WBI.…”

Section: Metabolic Interconversions Of Lipid Mediators and Their Contmentioning

confidence: 99%

Redox (phospho)lipidomics of signaling in inflammation and programmed cell death

Tyurina

Croix

Watkins

et al. 2019

Journal of Leukocyte Biology

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In addition to the known prominent role of polyunsaturated (phospho)lipids as structural blocks of biomembranes, there is an emerging understanding of another important function of these molecules as a highly diversified signaling language utilized for intra-and extracellular communications. Technological developments in high-resolution mass spectrometry facilitated the development of a new branch of metabolomics, redox lipidomics. Analysis of lipid peroxidation reactions has already identified specific enzymatic mechanisms responsible for the biosynthesis of several unique signals in response to inflammation and regulated cell death programs. Obtaining comprehensive information about millions of signals encoded by oxidized phospholipids, represented by thousands of interactive reactions and pleiotropic (patho)physiological effects, is a daunting task.However, there is still reasonable hope that significant discoveries, of at least some of the important contributors to the overall overwhelmingly complex network of interactions triggered by inflammation, will lead to the discovery of new small molecule regulators and therapeutic modalities. For example, suppression of the production of AA-derived pro-inflammatory mediators, HXA 3 and LTB 4, by an iPLA 2 inhibitor, R-BEL, mitigated injury associated with the activation of pro-inflammatory processes in animals exposed to whole-body irradiation. Further, technological developments promise to make redox lipidomics a powerful approach in the arsenal of diagnostic and therapeutic instruments for personalized medicine of inflammatory diseases and conditions. K E Y W O R D Seicosanoids, lipid mediators, lipoxygenase, Oxidized phospholipids, peroxidation, phospholipase A2, phospholipid hydrolysis

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Calcium-independent phospholipase A2γ (iPLA2γ) and its roles in cellular functions and diseases

Cited by 34 publications

References 56 publications

Homozygous Missense Variation in <b><i>PNPLA8</i></b> Causes Prenatal-Onset Severe Neurodegeneration

Homozygous Missense Variation in <b><i>PNPLA8</i></b> Causes Prenatal-Onset Severe Neurodegeneration

Antioxidant Synergy of Mitochondrial Phospholipase PNPLA8/iPLA2γ with Fatty Acid–Conducting SLC25 Gene Family Transporters

Redox (phospho)lipidomics of signaling in inflammation and programmed cell death

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