Moon 2012 J Biol Chem

Moon SH, Jenkins CM, Kiebish MA, Sims HF, Mancuso DJ, Gross RW (2012) Genetic ablation of calcium-independent phospholipase A2γ (iPLA2γ) attenuates calcium-induced opening of the mitochondrial permeability transition pore and resultant cytochrome c release. J Biol Chem [Epub ahead of print].

» PMID: 22778252 Open Access

Moon SH, Jenkins CM, Kiebish MA, Sims HF, Mancuso DJ, Gross RW (2012) J Biol Chem

Abstract: Herein, we demonstrate that calcium-independent phospholipase A_2γ (iPLA_2γ) is a critical mechanistic participant in the calcium-induced opening of the mitochondrial permeability transition pore (mPTP). Liver mitochondria from iPLA_2γ(-/-) mice were markedly resistant to calcium-induced swelling in the presence or absence of phosphate in comparisons to wild-type littermates. Furthermore, the iPLA_2γ enantioselective inhibitor (R)-BEL was markedly more potent than (S)-BEL in inhibiting mPTP opening in mitochondria from wild-type liver in comparison to hepatic mitochondria from iPLA_2γ(-/-) mice. Intriguingly, low micromolar concentrations of long chain fatty acyl-CoAs and the non-hydrolyzable thioether analog of palmitoyl-CoA markedly accelerated Ca²⁺-induced mPTP opening in liver mitochondria from wild-type mice. Addition of L-carnitine enabled the metabolic channeling of acyl-CoA through carnitine palmitoyl transferases (CPT I/II) and attenuated the palmitoyl-CoA-mediated amplification of calcium-induced mPTP opening. In contrast, mitochondria from iPLA_2γ(-/-) mice were insensitive to fatty acyl-CoA mediated augmentation of calcium-induced mPTP opening. Moreover, mitochondria from iPLA_2γ(-/-) mouse liver were resistant to Ca²⁺/t-butylhydroperoxide (TBH) induced mPTP opening in comparison to wild-type littermates. In support of these findings, cytochrome c release from iPLA_2γ(-/-) mitochondria was dramatically decreased in response to calcium in the presence or absence of either TBH or phenylarsine oxide (PAO) in comparisons to wild-type littermates. Collectively, these results identify iPLA_2γ as an important mechanistic component of the mPTP, define its downstream products as potent regulators of mPTP opening and demonstrate the integrated roles of mitochondrial bioenergetics and lipidomic flux in modulating mPTP opening promoting the activation of necrotic and necroapoptotic pathways of cell death. • Keywords: calcium-independent PLA_2γ, mitochondrial swelling, mitochondria permeability transition, reactive oxygen species, cytochrome c, acyl-CoA

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Stress:Cancer; Apoptosis; Cytochrome c"Cancer; Apoptosis; Cytochrome c" is not in the list (Cell death, Cryopreservation, Ischemia-reperfusion, Permeability transition, Oxidative stress;RONS, Temperature, Hypoxia, Mitochondrial disease) of allowed values for the "Stress" property., Genetic Defect; Knockdown; Overexpression"Genetic Defect; Knockdown; Overexpression" is not in the list (Cell death, Cryopreservation, Ischemia-reperfusion, Permeability transition, Oxidative stress;RONS, Temperature, Hypoxia, Mitochondrial disease) of allowed values for the "Stress" property.  Organism: Mouse  Tissue;cell: Hepatocyte; Liver"Hepatocyte; Liver" is not in the list (Heart, Skeletal muscle, Nervous system, Liver, Kidney, Lung;gill, Islet cell;pancreas;thymus, Endothelial;epithelial;mesothelial cell, Blood cells, Fat, ...) of allowed values for the "Tissue and cell" property.  Preparation: Isolated Mitochondria"Isolated Mitochondria" is not in the list (Intact organism, Intact organ, Permeabilized cells, Permeabilized tissue, Homogenate, Isolated mitochondria, SMP, Chloroplasts, Enzyme, Oxidase;biochemical oxidation, ...) of allowed values for the "Preparation" property.  Enzyme: TCA Cycle and Matrix Dehydrogenases"TCA Cycle and Matrix Dehydrogenases" is not in the list (Adenine nucleotide translocase, Complex I, Complex II;succinate dehydrogenase, Complex III, Complex IV;cytochrome c oxidase, Complex V;ATP synthase, Inner mt-membrane transporter, Marker enzyme, Supercomplex, TCA cycle and matrix dehydrogenases, ...) of allowed values for the "Enzyme" property., Complex II; Succinate Dehydrogenase"Complex II; Succinate Dehydrogenase" is not in the list (Adenine nucleotide translocase, Complex I, Complex II;succinate dehydrogenase, Complex III, Complex IV;cytochrome c oxidase, Complex V;ATP synthase, Inner mt-membrane transporter, Marker enzyme, Supercomplex, TCA cycle and matrix dehydrogenases, ...) of allowed values for the "Enzyme" property., Complex IV; Cytochrome c Oxidase"Complex IV; Cytochrome c Oxidase" is not in the list (Adenine nucleotide translocase, Complex I, Complex II;succinate dehydrogenase, Complex III, Complex IV;cytochrome c oxidase, Complex V;ATP synthase, Inner mt-membrane transporter, Marker enzyme, Supercomplex, TCA cycle and matrix dehydrogenases, ...) of allowed values for the "Enzyme" property., Marker Enzyme"Marker Enzyme" is not in the list (Adenine nucleotide translocase, Complex I, Complex II;succinate dehydrogenase, Complex III, Complex IV;cytochrome c oxidase, Complex V;ATP synthase, Inner mt-membrane transporter, Marker enzyme, Supercomplex, TCA cycle and matrix dehydrogenases, ...) of allowed values for the "Enzyme" property.  Regulation: Substrate; Glucose; TCA Cycle"Substrate; Glucose; TCA Cycle" is not in the list (Aerobic glycolysis, ADP, ATP, ATP production, AMP, Calcium, Coupling efficiency;uncoupling, Cyt c, Flux control, Inhibitor, ...) of allowed values for the "Respiration and regulation" property., Fatty Acid"Fatty Acid" is not in the list (Aerobic glycolysis, ADP, ATP, ATP production, AMP, Calcium, Coupling efficiency;uncoupling, Cyt c, Flux control, Inhibitor, ...) of allowed values for the "Respiration and regulation" property.  Coupling state: LEAK, OXPHOS, ETS"ETS" is not in the list (LEAK, ROUTINE, OXPHOS, ET) of allowed values for the "Coupling states" property. 

HRR: Oxygraph-2k, TIP2k