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 287:29837-50.|
Abstract: Herein, we demonstrate that calcium-independent phospholipase A2γ (iPLA2γ) is a critical mechanistic participant in the calcium-induced opening of the mitochondrial permeability transition pore (mPTP). Liver mitochondria from iPLA2γ(-/-) mice were markedly resistant to calcium-induced swelling in the presence or absence of phosphate in comparisons to wild-type littermates. Furthermore, the iPLA2γ 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 iPLA2γ(-/-) 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 iPLA2γ(-/-) mice were insensitive to fatty acyl-CoA mediated augmentation of calcium-induced mPTP opening. Moreover, mitochondria from iPLA2γ(-/-) 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 iPLA2γ(-/-) 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 iPLA2γ 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 PLA2γ, Mitochondrial swelling, Mitochondria permeability transition, Reactive oxygen species, Cytochrome c, Acyl-CoA
• O2k-Network Lab: US MO St Louis Gross RW
Labels: MiParea: Respiration
Stress:Cell death, Permeability transition Organism: Mouse Tissue;cell: Liver Preparation: Isolated mitochondria Enzyme: Complex II;succinate dehydrogenase, Complex IV;cytochrome c oxidase, Marker enzyme, TCA cycle and matrix dehydrogenases Regulation: Calcium, Cyt c, Substrate, Fatty acid Coupling state: LEAK, OXPHOS, ET Pathway: N, S, CIV HRR: Oxygraph-2k, TIP2k