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.

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

Zobrazit více v PubMed

Ježek P., Hlavatá L. Mitochondria in homeostasis of reactive oxygen species in cell, tissues, and organism. Int. J. Biochem. Cell Biol. 2005;37:2478–2503. doi: 10.1016/j.biocel.2005.05.013. PubMed DOI

Ježek P., Plecitá-Hlavatá L. Mitochondrial reticulum network dynamics in relation to oxidative stress, redox regulation, and hypoxia. Int. J. Biochem. Cell Biol. 2009;41:1790–1804. doi: 10.1016/j.biocel.2009.02.014. PubMed DOI

Ježek P., Olejár T., Smolková K., Ježek J., Dlasková A., Plecitá-Hlavatá L., Zelenka J., Špaček T., Engstová H., Pajuelo Reguera D., et al. Antioxidant and regulatory role of mitochondrial uncoupling protein UCP2 in pancreatic beta-cells. Physiol. Res. 2014;63(Suppl. 1):S73–S91. doi: 10.33549/physiolres.932633. PubMed DOI

Plecitá-Hlavatá L., Ježek P. Integration of superoxide formation and cristae morphology for mitochondrial redox signaling. Int. J. Biochem. Cell Biol. 2016;80:31–50. doi: 10.1016/j.biocel.2016.09.010. PubMed DOI

Ježek P., Holendová B., Garlid K.D., Jabůrek M. Mitochondrial uncoupling proteins: Subtle regulators of cellular redox signaling. Antioxidants Redox Signal. 2018;29:667–714. doi: 10.1089/ars.2017.7225. PubMed DOI PMC

Ježek P., Holendová B., Plecitá-Hlavatá L. Redox signaling from mitochondria: Signal propagation and its targets. Biomolecules. 2020;10:93. doi: 10.3390/biom10010093. PubMed DOI PMC

Ježek P., Holendová B., Jabůrek M., Tauber J., Dlasková A., Plecitá-Hlavatá L. The pancreatic β-cell: The perfect redox system. Antioxidants. 2021;10:197. doi: 10.3390/antiox10020197. PubMed DOI PMC

Ursini F., Maiorino M., Forman H.J. Redox homeostasis: The Golden Mean of healthy living. Redox Biol. 2016;8:205–215. doi: 10.1016/j.redox.2016.01.010. PubMed DOI PMC

Forman H.J. Redox signaling: An evolution from free radicals to aging. Free Radic. Biol. Med. 2016;97:398–407. doi: 10.1016/j.freeradbiomed.2016.07.003. PubMed DOI PMC

Skulachev V.P. Fatty acid circuit as a physiological mechanism of uncoupling of oxidative phosphorylation. FEBS Lett. 1991;294:158–162. doi: 10.1016/0014-5793(91)80658-P. PubMed DOI

Skulachev V.P. Uncoupling: New approaches to an old problem of bioenergetics. Biochim. Biophys. Acta Bioenerg. 1998;1363:100–124. doi: 10.1016/S0005-2728(97)00091-1. PubMed DOI

Bertholet A.M., Chouchani E.T., Kazak L., Angelin A., Fedorenko A., Long J.Z., Vidoni S., Garrity R., Cho J., Terada N., et al. H+ transport is an integral function of the mitochondrial ADP/ATP carrier. Nature. 2019;571:515–520. doi: 10.1038/s41586-019-1400-3. PubMed DOI PMC

Fedorenko A., Lishko P.V., Kirichok Y. Mechanism of fatty-acid-dependent UCP1 uncoupling in brown fat mitochondria. Cell. 2012;151:400–413. doi: 10.1016/j.cell.2012.09.010. PubMed DOI PMC

Ramanadham S., Tomader A., Ashley J.W., Bone R.N., Hancock W.D., Lei X. Calcium-independent phospholipases A2 and their roles in biological processes and diseases. J. Lipid Res. 2015;56:1643–1668. doi: 10.1194/jlr.R058701. PubMed DOI PMC

Murakami M., Sato H., Taketomi Y. Updating phospholipase A2 biology. Biomolecules. 2020;10:1457. doi: 10.3390/biom10101457. PubMed DOI PMC

Hara S., Yoda E., Sasaki Y., Nakatani Y., Kuwata H. Calcium-independent phospholipase A2γ (iPLA2γ) and its roles in cellular functions and diseases. Biochim. Biophys. Acta Mol. Cell Biol. Lipids. 2019;1864:861–868. doi: 10.1016/j.bbalip.2018.10.009. PubMed DOI

Ježek J., Jabůrek M., Zelenka J., Ježek P. Mitochondrial phospholipase A2 activated by reactive oxygen species in heart mitochondria induces mild uncoupling. Physiol. Res. 2010;59:737–747. doi: 10.33549/physiolres.931905. PubMed DOI

Jabůrek M., Ježek J., Zelenka J., Ježek P. Antioxidant activity by a synergy of redox-sensitive mitochondrial phospholipase A2 and uncoupling protein-2 in lung and spleen. Int. J. Biochem. Cell Biol. 2013;45:816–825. doi: 10.1016/j.biocel.2013.01.010. PubMed DOI

Ježek J., Dlasková A., Zelenka J., Jabůrek M., Ježek P. H2O2-activated mitochondrial phospholipase iPLA2γ prevents lipotoxic oxidative stress in synergy with UCP2, amplifies signaling via G-protein-coupled receptor GPR40, and regulates insulin secretion in pancreatic β-cells. Antioxid. Redox Signal. 2015;23:958–972. doi: 10.1089/ars.2014.6195. PubMed DOI PMC

Jabůrek M., Ježek J., Ježek P. Cytoprotective activity of mitochondrial uncoupling protein-2 in lung and spleen. FEBS Open Bio. 2018;8:692–701. doi: 10.1002/2211-5463.12410. PubMed DOI PMC

Murakami M., Taketomi Y., Miki Y., Sato H., Hirabayashi T., Yamamoto K. Recent progress in phospholipase A2 research: From cells to animals to humans. Prog. Lipid Res. 2011;50:152–192. doi: 10.1016/j.plipres.2010.12.001. PubMed DOI

Van Tienhoven M., Atkins J., Li Y., Glynn P. Human neuropathy target esterase catalyzes hydrolysis of membrane lipids. J. Biol. Chem. 2002;277:20942–20948. doi: 10.1074/jbc.M200330200. PubMed DOI

Baulande S., Lasnier F., Lucas M., Pairault J. Adiponutrin, a Transmembrane Protein Corresponding to a Novel Dietary- and Obesity-linked mRNA Specifically Expressed in the Adipose Lineage. J. Biol. Chem. 2001;276:33336–33344. doi: 10.1074/jbc.M105193200. PubMed DOI

Zimmermann R., Strauss J.G., Haemmerle G., Schoiswohl G., Birner-Gruenberger R., Riederer M., Lass A., Neuberger G., Eisenhaber F., Hermetter A., et al. Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase. Science. 2004;306:1383–1386. doi: 10.1126/science.1100747. PubMed DOI

Jenkins C.M., Mancuso D.J., Yan W., Sims H.F., Gibson B., Gross R.W. Identification, cloning, expression, and purification of three novel human calcium-independent phospholipase A2 family members possessing triacylglycerol lipase and acylglycerol transacylase activities. J. Biol. Chem. 2004;279:48968–48975. doi: 10.1074/jbc.M407841200. PubMed DOI

Mancuso D.J., Jenkins C.M., Sims H.F., Cohen J.M., Yang J., Gross R.W. Complex transcriptional and translational regulation of iPLA 2γ resulting in multiple gene products containing dual competing sites for mitochondrial or peroxisomal localization. Eur. J. Biochem. 2004;271:4709–4724. doi: 10.1111/j.1432-1033.2004.04435.x. PubMed DOI

Song H., Bao S., Lei X., Jin C., Zhang S., Turk J., Ramanadham S. Evidence for proteolytic processing and stimulated organelle redistribution of iPLA2β. Biochim. Biophys. Acta Mol. Cell Biol. Lipids. 2010;1801:547–558. doi: 10.1016/j.bbalip.2010.01.006. PubMed DOI PMC

Zhao Z., Zhang X., Zhao C., Choi J., Shi J., Song K., Turk J., Ma Z.A. Protection of pancreatic β-cells by group VIA phospholipase A 2-mediated repair of mitochondrial membrane peroxidation. Endocrinology. 2010;151:3038–3048. doi: 10.1210/en.2010-0016. PubMed DOI PMC

Moon S.H., Liu X., Cedars A.M., Yang K., Kiebish M.A., Joseph S.M., Kelley J., Jenkins C.M., Gross R.W. Heart failure-induced activation of phospholipase iPLA2γ generates hydroxyeicosatetraenoic acids opening the mitochondrial permeability transition pore. J. Biol. Chem. 2018;293:115–129. doi: 10.1074/jbc.RA117.000405. PubMed DOI PMC

Lio Y.C., Dennis E.A. Interfacial activation, lysophospholipase and transacylase activity of Group VI Ca2+-independent phospholipase A2. Biochim. Biophys. Acta Lipids Lipid Metab. 1998;1392:320–332. doi: 10.1016/S0005-2760(98)00049-6. PubMed DOI

Jenkins C.M., Yan W., Mancuso D.J., Gross R.W. Highly selective hydrolysis of fatty acyl-CoAs by calcium-independent phospholipase A2β: Enzyme autoacylation and acyl-CoA-mediated reversal of calmodulin inhibition of phospholipase A2 activity. J. Biol. Chem. 2006;281:15615–15624. doi: 10.1074/jbc.M511623200. PubMed DOI

Ma Z., Ramanadham S., Kempe K., Chi X.S., Ladenson J., Turk J. Pancreatic islets express a Ca2+-independent phospholipase A2 enzyme that contains a repeated structural motif homologous to the integral membrane protein binding domain of ankyrin. J. Biol. Chem. 1997;272:11118–11127. doi: 10.1074/jbc.272.17.11118. PubMed DOI

Malley K.R., Koroleva O., Miller I., Sanishvili R., Jenkins C.M., Gross R.W., Korolev S. The structure of iPLA2β reveals dimeric active sites and suggests mechanisms of regulation and localization. Nat. Commun. 2018;9:765. doi: 10.1038/s41467-018-03193-0. PubMed DOI PMC

Bucher D., Hsu Y.H., Mouchlis V.D., Dennis E.A., McCammon J.A. Insertion of the Ca2+-Independent Phospholipase A2 into a Phospholipid Bilayer via Coarse-Grained and Atomistic Molecular Dynamics Simulations. PLoS Comput. Biol. 2013;9:e1003156. doi: 10.1371/journal.pcbi.1003156. PubMed DOI PMC

Yan W., Jenkins C.M., Han X., Mancuso D.J., Sims H.F., Yang K., Gross R.W. The highly selective production of 2-arachidonoyl lysophosphatidylcholine catalyzed by purified calcium-independent phospholipase A2γ: Identification of a novel enzymatic mediator for the generation of a key branch point intermediate in eicosanoid signali. J. Biol. Chem. 2005;280:26669–26679. doi: 10.1074/jbc.M502358200. PubMed DOI

Mancuso D.J., Han X., Jenkins C.M., Lehman J.J., Sambandam N., Sims H.F., Yang J., Yan W., Yang K., Green K., et al. Dramatic accumulation of triglycerides and precipitation of cardiac hemodynamic dysfunction during brief caloric restriction in transgenic myocardium expressing human calcium-independent phospholipase A2γ. J. Biol. Chem. 2007;282:9216–9227. doi: 10.1074/jbc.M607307200. PubMed DOI

Mancuso D.J., Jenkins C.M., Gross R.W. The genomic organization, complete mRNA sequence, cloning, and expression of a novel human intracellular membrane-associated calcium-independent phospholipase A(2) J. Biol. Chem. 2000;275:9937–9945. doi: 10.1074/jbc.275.14.9937. PubMed DOI

Tanaka H., Takeya R., Sumimoto H. A novel intracellular membrane-bound calcium-independent phospholipase A2. Biochem. Biophys. Res. Commun. 2000;272:320–326. doi: 10.1006/bbrc.2000.2776. PubMed DOI

Liu X., Sims H.F., Jenkins C.M., Guan S., Dilthey B.G., Gross R.W. 12-LOX catalyzes the oxidation of 2-arachidonoyl-lysolipids in platelets generating eicosanoid-lysolipids that are attenuated by iPLA2γ knockout. J. Biol. Chem. 2020;295:5307–5320. doi: 10.1074/jbc.RA119.012296. PubMed DOI PMC

Jabůrek M., Holendová B., Průchová P., Ježek P. Cardiolipin hydroperoxides are both substrates and redox activators of phospholipase iPLA2γ. Free Radic. Biol. Med. 2018;120:S65. doi: 10.1016/j.freeradbiomed.2018.04.215. DOI

Kühlbrandt W. Structure and function of mitochondrial membrane protein complexes. BMC Biol. 2015;13:89. doi: 10.1186/s12915-015-0201-x. PubMed DOI PMC

Dlasková A., Špaček T., Engstová H., Špačková J., Schröfel A., Holendová B., Smolková K., Plecitá-Hlavatá L., Ježek P. Mitochondrial cristae narrowing upon higher 2-oxoglutarate load. Biochim. Biophys. Acta Bioenerg. 2019;1860:659–678. doi: 10.1016/j.bbabio.2019.06.015. PubMed DOI

Tanaka H., Minakami R., Kanaya H., Sumimoto H. Catalytic residues of group VIB calcium-independent phospholipase A 2 (iPLA2γ) Biochem. Biophys. Res. Commun. 2004;320:1284–1290. doi: 10.1016/j.bbrc.2004.05.225. PubMed DOI

Liu G.-Y.Y., Moon S.H., Jenkins C.M., Li M., Sims H.F., Guan S., Gross R.W., Ho Moon S., Jenkins C.M., Li M., et al. The phospholipase iPLA2 is a major mediator releasing oxidized aliphatic chains from cardiolipin, integrating mitochondrial bioenergetics and signaling. J. Biol. Chem. 2017;292:10672–10684. doi: 10.1074/jbc.M117.783068. PubMed DOI PMC

Yoda E., Hachisu K., Taketomi Y., Yoshida K., Nakamura M., Ikeda K., Taguchi R., Nakatani Y., Kuwata H., Murakami M., et al. Mitochondrial dysfunction and reduced prostaglandin synthesis in skeletal muscle of Group VIB Ca2+-independent phospholipase A2gamma-deficient mice. J. Lipid Res. 2010;51:3003–3015. doi: 10.1194/jlr.M008060. PubMed DOI PMC

Moon S.H., Dilthey B.G., Liu X., Guan S., Sims H.F., Gross R.W. High-Fat diet activates liver iPLA2γ generating eicosanoids that mediate metabolic stress. J. Lipid Res. 2021;62:100052. doi: 10.1016/j.jlr.2021.100052. PubMed DOI PMC

Jabůrek M., Garlid K.D. Reconstitution of recombinant uncoupling proteins. UCP1, -2, and -3 have similar affinities for ATP and are unaffected by coenzyme Q10. J. Biol. Chem. 2003;278:25825–25831. doi: 10.1074/jbc.M302126200. PubMed DOI

Jabůrek M., Vařecha M., Gimeno R.E., Dembski M., Ježek P., Zhang M., Burn P., Tartaglia L.A., Garlid K.D. Transport function and regulation of mitochondrial uncoupling proteins 2 and 3. J. Biol. Chem. 1999;274:26003–26007. doi: 10.1074/jbc.274.37.26003. PubMed DOI

Jabůrek M., Miyamoto S., Di Mascio P., Garlid K.D., Ježek P. Hydroperoxy fatty acid cycling mediated by mitochondrial uncoupling protein UCP2. J. Biol. Chem. 2004;279:53097–53102. doi: 10.1074/jbc.M405339200. PubMed DOI

Bertholet A.M., Kazak L., Chouchani E.T., Bogaczyńska M.G., Paranjpe I., Wainwright G.L., Bétourné A., Kajimura S., Spiegelman B.M., Kirichok Y. Mitochondrial Patch Clamp of Beige Adipocytes Reveals UCP1-Positive and UCP1-Negative Cells Both Exhibiting Futile Creatine Cycling. Cell Metab. 2017;25:811–822.e4. doi: 10.1016/j.cmet.2017.03.002. PubMed DOI PMC

Wojtczak L., Wiȩckowski M.R. The mechanisms of fatty acid-induced proton permeability of the inner mitochondrial membrane. J. Bioenerg. Biomembr. 1999;31:447–455. doi: 10.1023/A:1005444322823. PubMed DOI

Wojtczak L., Wiȩckowski M.R., Schönfeld P. Protonophoric activity of fatty acid analogs and derivatives in the inner mitochondrial membrane: A further argument for the fatty acid cycling model. Arch. Biochem. Biophys. 1998;357:76–84. doi: 10.1006/abbi.1998.0777. PubMed DOI

Brustovetsky N., Klingenberg M. The reconstituted ADP/ATP carrier can mediate H+ transport by free fatty acids, which is further stimulated by mersalyl. J. Biol. Chem. 1994;269:27329–27336. doi: 10.1016/S0021-9258(18)46989-X. PubMed DOI

Capaldi R.A. Arrangement of proteins in the mitochondrial inner membrane. BBA Rev. Biomembr. 1982;694:291–306. doi: 10.1016/0304-4157(82)90009-0. PubMed DOI

Elimam H., Papillon J., Kaufman D.R., Guillemette J., Aoudjit L., Gross R.W., Takano T., Cybulsky A.V. Genetic ablation of calcium-independent phospholipase A2γ induces glomerular injury in mice. J. Biol. Chem. 2016;291:14468–14482. doi: 10.1074/jbc.M115.696781. PubMed DOI PMC

Elimam H., Papillon J., Guillemette J., Navarro-Betancourt J.R., Cybulsky A.V. Genetic Ablation of Calcium-independent Phospholipase A2γ Exacerbates Glomerular Injury in Adriamycin Nephrosis in Mice. Sci. Rep. 2019;9:16229. doi: 10.1038/s41598-019-52834-x. PubMed DOI PMC

Peterson B., Knotts T., Cummings B.S. Involvement of Ca2+-independent phospholipase A2 isoforms in oxidant-induced neural cell death. Neurotoxicology. 2007;28:150–160. doi: 10.1016/j.neuro.2006.09.006. PubMed DOI

Rauckhorst A.J., Pfeiffer D.R., Broekemeier K.M. The iPLA2γ is identified as the membrane potential sensitive phospholipase in liver mitochondria. FEBS Lett. 2015;589:2367–2371. doi: 10.1016/j.febslet.2015.07.016. PubMed DOI

Garlid K.D., Jabůrek M., Ježek P. Mechanism of uncoupling protein action. Biochem. Soc. Trans. 2001;29:803–806. doi: 10.1042/bst0290803. PubMed DOI

Skulachev V.P. Membrane-linked systems preventing superoxide formation. Biosci. Rep. 1997;17:347–366. doi: 10.1023/A:1027344914565. PubMed DOI

Jastroch M., Divakaruni A.S., Mookerjee S., Treberg J.R., Brand M.D. Mitochondrial proton and electron leaks. Essays Biochem. 2010;47:53–67. doi: 10.1042/bse0470053. PubMed DOI PMC

Nicholls D.G. The Effective Proton Conductance of the Inner Membrane of Mitochondria from Brown Adipose Tissue: Dependency on Proton Electrochemical Potential Gradient. Eur. J. Biochem. 1977;77:349–356. doi: 10.1111/j.1432-1033.1977.tb11674.x. PubMed DOI

Ježek P., Žáčková M., Růžička M., Škobisová E., Jabůrek M. Mitochondrial Uncoupling Proteins—Facts and Fantasies. Physiol. Res. 2004;53:S199–S211. PubMed

Garlid K.D., Beavis A.D., Ratkje S.K. On the nature of ion leaks in energy-transducing membranes. BBA Bioenerg. 1989;976:109–120. doi: 10.1016/S0005-2728(89)80219-1. PubMed DOI

Garlid K.D., Orosz D.E., Modrianský M., Vassanelli S., Ježek P. On the mechanism of fatty acid-induced proton transport by mitochondrial uncoupling protein. J. Biol. Chem. 1996;271:2615–2620. doi: 10.1074/jbc.271.5.2615. PubMed DOI

Jabůrek M., Vařecha M., Ježek P., Garlid K.D. Alkylsulfonates as probes of uncoupling protein transport mechanism. Ion pair transport demonstrates that direct H+ translocation by UCP1 is not necessary for uncoupling. J. Biol. Chem. 2001;276:31897–31905. doi: 10.1074/jbc.M103507200. PubMed DOI

Brand M.D. Mitochondrial generation of superoxide and hydrogen peroxide as the source of mitochondrial redox signaling. Free Radic. Biol. Med. 2016;100:14–31. doi: 10.1016/j.freeradbiomed.2016.04.001. PubMed DOI

Korshunov S.S., Skulachev V.P., Starkov A.A. High protonic potential actuates a mechanism of production of reactive oxygen species in mitochondria. FEBS Lett. 1997;416:15–18. doi: 10.1016/S0014-5793(97)01159-9. PubMed DOI

Vyssokikh M.Y., Holtze S., Averina O.A., Lyamzaev K.G., Panteleeva A.A., Marey M.V., Zinovkin R.A., Severin F.F., Skulachev M.V., Fasel N., et al. Mild depolarization of the inner mitochondrial membrane is a crucial component of an anti-aging program. Proc. Natl. Acad. Sci. USA. 2020;117:6491–6501. doi: 10.1073/pnas.1916414117. PubMed DOI PMC

Komlódi T., Geibl F.F., Sassani M., Ambrus A., Tretter L. Membrane potential and delta pH dependency of reverse electron transport-associated hydrogen peroxide production in brain and heart mitochondria. J. Bioenerg. Biomembr. 2018;50:355–365. doi: 10.1007/s10863-018-9766-8. PubMed DOI PMC

Rupprecht A., Sokolenko E.A., Beck V., Ninnemann O., Jabůrek M., Trimbuch T., Klishin S.S., Ježek P., Skulachev V.P., Pohl E.E. Role of the transmembrane potential in the membrane proton leak. Biophys. J. 2010;98:1503–1511. doi: 10.1016/j.bpj.2009.12.4301. PubMed DOI PMC

Rana M., De Coo I., Diaz F., Smeets H., Moraes C.T. An out-of-frame cytochrome b gene deletion from a patient with parkinsonism is associated with impaired complex III assembly and an increase in free radical production. Ann. Neurol. 2000;48:774–781. doi: 10.1002/1531-8249(200011)48:5<774::AID-ANA11>3.0.CO;2-I. PubMed DOI

Borek A., Kuleta P., Ekiert R., Pietras R., Sarewicz M., Osyczka A. Mitochondrial disease-related mutation G167P in cytochrome b of Rhodobacter capsulatus cytochrome bc1 (S151P in human) affects the equilibrium distribution of [2Fe-2S] cluster and generation of superoxide. J. Biol. Chem. 2015;290:23781–23792. doi: 10.1074/jbc.M115.661314. PubMed DOI PMC

Yin Z., Burger N., Kula-Alwar D., Aksentijević D., Bridges H.R., Prag H.A., Grba D.N., Viscomi C., James A.M., Mottahedin A., et al. Structural basis for a complex I mutation that blocks pathological ROS production. Nat. Commun. 2021;12:707. doi: 10.1038/s41467-021-20942-w. PubMed DOI PMC

Kukat A., Dogan S.A., Edgar D., Mourier A., Jacoby C., Maiti P., Mauer J., Becker C., Senft K., Wibom R., et al. Loss of UCP2 Attenuates Mitochondrial Dysfunction without Altering ROS Production and Uncoupling Activity. PLoS Genet. 2014;10:e1004385. doi: 10.1371/journal.pgen.1004385. PubMed DOI PMC

Andreyev A.Y., Bondareva T.O., Dedukhova V.I., Mokhova E.N., Skulachev V.P., Tsofina L.M., Volkov N.I., Vygodina T.V. The ATP/ADP-antiporter is involved in the uncoupling effect of fatty acids on mitochondria. Eur. J. Biochem. 1989;182:585–592. doi: 10.1111/j.1432-1033.1989.tb14867.x. PubMed DOI

Engstová H., Žáčková M., Růžiča M., Meinhardt A., Hanuš J., Krämer R., Ježek P. Natural and Azido Fatty Acids Inhibit Phosphate Transport and Activate Fatty Acid Anion Uniport Mediated by the Mitochondrial Phosphate Carrier. J. Biol. Chem. 2001;276:4683–4691. doi: 10.1074/jbc.M009409200. PubMed DOI

Samartsev V.N., Smirnov A.V., Zeldi I.P., Markova O.V., Mokhova E.N., Skulachev V.P. Involvement of aspartate/glutamate antiporter in fatty acid-induced uncoupling of liver mitochondria. Biochim. Biophys. Acta Bioenerg. 1997;1319:251–257. doi: 10.1016/S0005-2728(96)00166-1. PubMed DOI

Samartsev V.N., Mokhova E.N., Skulachev V.P. The pH-dependent reciprocal changes in contributions of ADP/ATP antiporter and aspartate/glutamate antiporter to the fatty acid-induced uncoupling. FEBS Lett. 1997;412:179–182. doi: 10.1016/S0014-5793(97)00667-4. PubMed DOI

Khailova L.S., Prikhodko E.A., Dedukhova V.I., Mokhova E.N., Popov V.N., Skulachev V.P. Participation of ATP/ADP antiporter in oleate- and oleate hydroperoxide-induced uncoupling suppressed by GDP and carboxyatractylate. Biochim. Biophys. Acta Bioenerg. 2006;1757:1324–1329. doi: 10.1016/j.bbabio.2006.04.024. PubMed DOI

Korshunov S.S., Korkina O.V., Ruuge E.K., Skulachev V.P., Starkov A.A. Fatty acids as natural uncouplers preventing generation of O(·-)2 and H2O2 by mitochondria in the resting state. FEBS Lett. 1998;435:215–218. doi: 10.1016/S0014-5793(98)01073-4. PubMed DOI

Shabalina I.G., Kramarova T.V., Nedergaard J., Cannon B. Carboxyatractyloside effects on brown-fat mitochondria imply that the adenine nucleotide translocator isoforms ANT1 and ANT2 may be responsible for basal and fatty-acid-induced uncoupling respectively. Biochem. J. 2006;399:405–414. doi: 10.1042/BJ20060706. PubMed DOI PMC

Kreiter J., Rupprecht A., Škulj S., Brkljača Z., Žuna K., Knyazev D.G., Bardakji S., Vazdar M., Pohl E.E. Ant1 activation and inhibition patterns support the fatty acid cycling mechanism for proton transport. Int. J. Mol. Sci. 2021;22:2490. doi: 10.3390/ijms22052490. PubMed DOI PMC

Nordmann C., Strokin M., Schönfeld P., Reiser G. Putative roles of Ca2+-independent phospholipase A2 in respiratory chain-associated ROS production in brain mitochondria: Infuence of docosahexaenoic acid and bromoenol lactone. J. Neurochem. 2014;131:163–176. doi: 10.1111/jnc.12789. PubMed DOI

Průchová P., Leguina-Ruzzi A., Galkin A., Ježek P., Jabůrek M. Antioxidant activity of calcium-independent phospholipase A2γ in brain mitochondria. Free Radic. Biol. Med. 2018;128:S86. doi: 10.1016/j.freeradbiomed.2018.10.198. DOI

Winterbourn C.C. Are free radicals involved in thiol-based redox signaling? Free Radic. Biol. Med. 2015;80:164–170. doi: 10.1016/j.freeradbiomed.2014.08.017. PubMed DOI

Requejo R., Hurd T.R., Costa N.J., Murphy M.P. Cysteine residues exposed on protein surfaces are the dominant intramitochondrial thiol and may protect against oxidative damage. FEBS J. 2010;277:1465–1480. doi: 10.1111/j.1742-4658.2010.07576.x. PubMed DOI PMC

Nietzel T., Mostertz J., Hochgräfe F., Schwarzländer M. Redox regulation of mitochondrial proteins and proteomes by cysteine thiol switches. Mitochondrion. 2017;33:72–83. doi: 10.1016/j.mito.2016.07.010. PubMed DOI

Poole L.B. The basics of thiols and cysteines in redox biology and chemistry. Free Radic. Biol. Med. 2015;80:148–157. doi: 10.1016/j.freeradbiomed.2014.11.013. PubMed DOI PMC

Paulsen C.E., Carroll K.S. Cysteine-mediated redox signaling: Chemistry, biology, and tools for discovery. Chem. Rev. 2013;113:4633–4679. doi: 10.1021/cr300163e. PubMed DOI PMC

Poole L.B., Furdui C.M., King S.B. Introduction to approaches and tools for the evaluation of protein cysteine oxidation. Essays Biochem. 2020;64:1–17. doi: 10.1042/EBC20190050. PubMed DOI PMC

Rhee S.G., Woo H.A., Kang D. The Role of Peroxiredoxins in the Transduction of H2O2 Signals. Antioxidants Redox Signal. 2018;28:537–557. doi: 10.1089/ars.2017.7167. PubMed DOI

Codreanu S.G., Liebler D.C. Novel approaches to identify protein adducts produced by lipid peroxidation. Free Radic. Res. 2015;49:881–887. doi: 10.3109/10715762.2015.1019348. PubMed DOI PMC

Higdon A., Diers A.R., Oh J.Y., Landar A., Darley-Usmar V.M. Cell signalling by reactive lipid species: New concepts and molecular mechanisms. Biochem. J. 2012;442:453–464. doi: 10.1042/BJ20111752. PubMed DOI PMC

Xiao H., Jedrychowski M.P., Schweppe D.K., Huttlin E.L., Yu Q., Heppner D.E., Li J., Long J., Mills E.L., Szpyt J., et al. A Quantitative Tissue-Specific Landscape of Protein Redox Regulation during Aging. Cell. 2020;180:968–983.e24. doi: 10.1016/j.cell.2020.02.012. PubMed DOI PMC

Elimam H., Papillon J., Takano T., Cybulsky A.V. Complement-mediated activation of calcium-independent phospholipase A 2γ: Role of protein kinases and phosphorylation. J. Biol. Chem. 2013;288:3871–3885. doi: 10.1074/jbc.M112.396614. PubMed DOI PMC

Sadžak A., Mravljak J., Maltar-Strmečki N., Arsov Z., Baranović G., Erceg I., Kriechbaum M., Strasser V., Přibyl J., Šegota S. The structural integrity of the model lipid membrane during induced lipid peroxidation: The role of flavonols in the inhibition of lipid peroxidation. Antioxidants. 2020;9:430. doi: 10.3390/antiox9050430. PubMed DOI PMC

Cozza G., Rossetto M., Bosello-Travain V., Maiorino M., Roveri A., Toppo S., Zaccarin M., Zennaro L., Ursini F. Glutathione peroxidase 4-catalyzed reduction of lipid hydroperoxides in membranes: The polar head of membrane phospholipids binds the enzyme and addresses the fatty acid hydroperoxide group toward the redox center. Free Radic. Biol. Med. 2017;112:1–11. doi: 10.1016/j.freeradbiomed.2017.07.010. PubMed DOI

Tsubone T.M., Junqueira H.C., Baptista M.S., Itri R. Contrasting roles of oxidized lipids in modulating membrane microdomains. Biochim. Biophys. Acta Biomembr. 2019;1861:660–669. doi: 10.1016/j.bbamem.2018.12.017. PubMed DOI

Sevanian A., Wratten M., McLeod L.L., Kim E. Lipid peroxidation and phospholipase A2 activity in liposomes composed of unsaturated phospholipids: A structural basis for enzyme activation. Biochim. Biophys. Acta. 1988;961:316–327. doi: 10.1016/0005-2760(88)90079-3. PubMed DOI

McLean L.R., Hagaman K.A., Davidson W.S. Role of lipid structure in the activation of phospholipase A2 by peroxidized phospholipids. Lipids. 1993;28:505–509. doi: 10.1007/BF02536081. PubMed DOI

Niki E., Yoshida Y., Saito Y., Noguchi N. Lipid peroxidation: Mechanisms, inhibition, and biological effects. Biochem. Biophys. Res. Commun. 2005;338:668–676. doi: 10.1016/j.bbrc.2005.08.072. PubMed DOI

Pennington E.R., Funai K., Brown D.A., Shaikh S.R. The role of cardiolipin concentration and acyl chain composition on mitochondrial inner membrane molecular organization and function. Biochim. Biophys. Acta Mol. Cell Biol. Lipids. 2019;1864:1039–1052. doi: 10.1016/j.bbalip.2019.03.012. PubMed DOI PMC

Tatsuta T., Langer T. Intramitochondrial phospholipid trafficking. Biochim. Biophys. Acta Mol. Cell Biol. Lipids. 2017;1862:81–89. doi: 10.1016/j.bbalip.2016.08.006. PubMed DOI

Kiebish M.A., Yang K., Liu X., Mancuso D.J., Guan S., Zhao Z., Sims H.F., Cerqua R., Cade W.T., Han X., et al. Dysfunctional cardiac mitochondrial bioenergetic, lipidomic, and signaling in a murine model of Barth syndrome. J. Lipid Res. 2013;54:1312–1325. doi: 10.1194/jlr.M034728. PubMed DOI PMC

Casares D., Escribá P.V., Rosselló C.A. Membrane lipid composition: Effect on membrane and organelle structure, function and compartmentalization and therapeutic avenues. Int. J. Mol. Sci. 2019;20:2167. doi: 10.3390/ijms20092167. PubMed DOI PMC

Valianpour F., Wanders R.J.A., Barth P.G., Overmars H., Van Gennip A.H. Quantitative and compositional study of cardiolipin in platelets by electrospray ionization mass spectrometry: Application for the identification of Barth syndrome patients. Clin. Chem. 2002;48:1390–1397. doi: 10.1093/clinchem/48.9.1390. PubMed DOI

Kiebish M.A., Han X., Cheng H., Chuang J.H., Seyfried T.N. Cardiolipin and electron transport chain abnormalities in mouse brain tumor mitochondria: Lipidomic evidence supporting the Warburg theory of cancer. J. Lipid Res. 2008;49:2545–2556. doi: 10.1194/jlr.M800319-JLR200. PubMed DOI PMC

Tyurina Y.Y., Shrivastava I., Tyurin V.A., Mao G., Dar H.H., Watkins S., Epperly M., Bahar I., Shvedova A.A., Pitt B., et al. Only a Life Lived for Others Is Worth Living: Redox Signaling by Oxygenated Phospholipids in Cell Fate Decisions. Antioxidants Redox Signal. 2018;29:1333–1358. doi: 10.1089/ars.2017.7124. PubMed DOI PMC

Ikon N., Ryan R.O. Cardiolipin and mitochondrial cristae organization. Biochim. Biophys. Acta Biomembr. 2017;1859:1156–1163. doi: 10.1016/j.bbamem.2017.03.013. PubMed DOI PMC

Ban T., Heymann J.A.W., Song Z., Hinshaw J.E., Chan D.C. OPA1 disease alleles causing dominant optic atrophy have defects in cardiolipin-stimulated GTP hydrolysis and membrane tubulation. Hum. Mol. Genet. 2010;19:2113–2122. doi: 10.1093/hmg/ddq088. PubMed DOI PMC

Jussupow A., Di Luca A., Kaila V.R.I. How cardiolipin modulates the dynamics of respiratory complex I. Sci. Adv. 2019;5:eaav1850. doi: 10.1126/sciadv.aav1850. PubMed DOI PMC

Malkamäki A., Sharma V. Atomistic insights into cardiolipin binding sites of cytochrome c oxidase. Biochim. Biophys. Acta Bioenerg. 2019;1860:224–232. doi: 10.1016/j.bbabio.2018.11.004. PubMed DOI

Duncan A.L., Ruprecht J.J., Kunji E.R.S., Robinson A.J. Cardiolipin dynamics and binding to conserved residues in the mitochondrial ADP/ATP carrier. Biochim. Biophys. Acta Biomembr. 2018;1860:1035–1045. doi: 10.1016/j.bbamem.2018.01.017. PubMed DOI PMC

Gasanov S.E., Kim A.A., Yaguzhinsky L.S., Dagda R.K. Non-bilayer structures in mitochondrial membranes regulate ATP synthase activity. Biochim. Biophys. Acta Biomembr. 2018;1860:586–599. doi: 10.1016/j.bbamem.2017.11.014. PubMed DOI PMC

Khosravi S., Harner M.E. The MICOS complex, a structural element of mitochondria with versatile functions. Biol. Chem. 2020;401:765–778. doi: 10.1515/hsz-2020-0103. PubMed DOI

Kozjak-Pavlovic V. The MICOS complex of human mitochondria. Cell Tissue Res. 2017;367:83–93. doi: 10.1007/s00441-016-2433-7. PubMed DOI

Hsu Y.H., Dumlao D.S., Cao J., Dennis E.A. Assessing Phospholipase A2 Activity toward Cardiolipin by Mass Spectrometry. PLoS ONE. 2013;8:e59267. doi: 10.1371/annotation/47607b18-ed69-4a08-8619-60c39bd83a13. PubMed DOI PMC

Gonzalez-Baro M.R., Coleman R.A. Mitochondrial acyltransferases and glycerophospholipid metabolism. Biochim. Biophys. Acta Mol. Cell Biol. Lipids. 2017;1862:49–55. doi: 10.1016/j.bbalip.2016.06.023. PubMed DOI

Cipolat S., Rudka T., Hartmann D., Costa V., Serneels L., Craessaerts K., Metzger K., Frezza C., Annaert W., D’Adamio L., et al. Mitochondrial Rhomboid PARL Regulates Cytochrome c Release during Apoptosis via OPA1-Dependent Cristae Remodeling. Cell. 2006;126:163–175. doi: 10.1016/j.cell.2006.06.021. PubMed DOI

Lopaschuk G.D., Ussher J.R., Folmes C.D.L., Jaswal J.S., Stanley W.C. Myocardial fatty acid metabolism in health and disease. Physiol. Rev. 2010;90:207–258. doi: 10.1152/physrev.00015.2009. PubMed DOI

Ford D.A., Hazen S.L., Saffitz J.E., Gross R.W. The rapid and reversible activation of a calcium-independent plasmalogen-selective phospholipase A2 during myocardial ischemia. J. Clin. Investig. 1991;88:331–335. doi: 10.1172/JCI115296. PubMed DOI PMC

Williams S.D., Gottlieb R.A. Inhibition of mitochondrial calcium-independent phospholipase A2 (iPLA2) attenuates mitochondrial phospholipid loss and is cardioprotective. Biochem. J. 2002;362:23–32. doi: 10.1042/bj3620023. PubMed DOI PMC

Moon S.H., Mancuso D.J., Sims H.F., Liu X., Nguyen A.L., Yang K., Guan S., Dilthey B.G., Jenkins C.M., Weinheimer C.J., et al. Cardiac myocyte-specific knock-out of calcium-independent phospholipase A2γ (iPLA2γ) decreases oxidized fatty acids during ischemia/reperfusion and reduces infarct size. J. Biol. Chem. 2016;291:19687–19700. doi: 10.1074/jbc.M116.740597. PubMed DOI PMC

Garlid A.O., Jabůrek M., Jacobs J.P., Garlid K.D. Mitochondrial reactive oxygen species: Which ROS signals cardioprotection? AJP Hear. Circ. Physiol. 2013;305:H960–H968. doi: 10.1152/ajpheart.00858.2012. PubMed DOI PMC

Wolf M.J., Izumi Y., Zorumski C.F., Gross R.W. Long-term potentiation requires activation of calcium-independent phospholipase A2. FEBS Lett. 1995;377:358–362. doi: 10.1016/0014-5793(95)01371-7. PubMed DOI

Adibhatla R.M., Hatcher J.F. Phospholipase A2, reactive oxygen species, and lipid peroxidation in cerebral ischemia. Free Radic. Biol. Med. 2006;40:376–387. doi: 10.1016/j.freeradbiomed.2005.08.044. PubMed DOI

Adibhatla R.M., Hatcher J.F. Phospholipase A2, reactive oxygen species, and lipid peroxidation in CNS pathologies. J. Biochem. Mol. Biol. 2008;41:560–567. doi: 10.5483/BMBRep.2008.41.8.560. PubMed DOI PMC

Mancuso D.J., Kotzbauer P., Wozniak D.F., Sims H.F., Jenkins C.M., Guan S., Han X., Yang K., Sun G., Malik I., et al. Genetic ablation of calcium-independent phospholipase A2γ leads to alterations in hippocampal cardiolipin content and molecular species distribution, mitochondrial degeneration, autophagy, and cognitive dysfunction. J. Biol. Chem. 2009;284:35632–35644. doi: 10.1074/jbc.M109.055194. PubMed DOI PMC

Chao H., Liu Y., Fu X., Xu X., Bao Z., Lin C., Li Z., Liu Y., Wang X., You Y., et al. Lowered iPLA2γ activity causes increased mitochondrial lipid peroxidation and mitochondrial dysfunction in a rotenone-induced model of Parkinson’s disease. Exp. Neurol. 2018;300:74–86. doi: 10.1016/j.expneurol.2017.10.031. PubMed DOI

Chao H., Anthonymuthu T.S., Kenny E.M., Amoscato A.A., Cole L.K., Hatch G.M., Ji J., Kagan V.E., Bayır H. Disentangling oxidation/hydrolysis reactions of brain mitochondrial cardiolipins in pathogenesis of traumatic injury. JCI Insight. 2018;3:e97677. doi: 10.1172/jci.insight.97677. PubMed DOI PMC

Ježek P., Jabůrek M., Porter R.K. Uncoupling mechanism and redox regulation of mitochondrial uncoupling protein 1 (UCP1) Elsevier B.V. 2019;1860:259–269. doi: 10.1016/j.bbabio.2018.11.007. PubMed DOI

Mancuso D.J., Sims H.F., Han X., Jenkins C.M., Shao P.G., Yang K., Sung H.M., Pietka T., Abumrad N.A., Schlesinger P.H., et al. Genetic ablation of calcium-independent phospholipase A2γ leads to alterations in mitochondrial lipid metabolism and function resulting in a deficient mitochondrial bioenergetic phenotype. J. Biol. Chem. 2007;282:34611–34622. doi: 10.1074/jbc.M707795200. PubMed DOI PMC

Schweizer S., Liebisch G., Oeckl J., Hoering M., Seeliger C., Schiebel C., Klingenspor M., Ecker J. The lipidome of primary murine white, brite, and brown adipocytes—Impact of betaadrenergic stimulation. PLoS Biol. 2019;17:e3000412. doi: 10.1371/journal.pbio.3000412. PubMed DOI PMC

Chouchani E.T., Kazak L., Jedrychowski M.P., Lu G.Z., Erickson B.K., Szpyt J., Pierce K.A., Laznik-Bogoslavski D., Vetrivelan R., Clish C.B., et al. Mitochondrial ROS regulate thermogenic energy expenditure and sulfenylation of UCP1. Nature. 2016;532:112–116. doi: 10.1038/nature17399. PubMed DOI PMC

Mitochondria to plasma membrane redox signaling is essential for fatty acid β-oxidation-driven insulin secretion

Mitochondrial Physiology of Cellular Redox Regulations

Mitochondrial Cristae Morphology Reflecting Metabolism, Superoxide Formation, Redox Homeostasis, and Pathology

Membrane Lipid Reshaping Underlies Oxidative Stress Sensing by the Mitochondrial Proteins UCP1 and ANT1

Contribution of Mitochondria to Insulin Secretion by Various Secretagogues

Antioxidant Role and Cardiolipin Remodeling by Redox-Activated Mitochondrial Ca2+-Independent Phospholipase A2γ in the Brain

Mitochondrial Redox Regulations and Redox Biology of Mitochondria