title: Suppression of mitochondrial function by oxidatively truncated phospholipids is reversible, aided by bid, and suppressed by Bcl-XL.
abstract: Oxidatively truncated phospholipids are present in atherosclerotic lesions, apoptotic cells, and oxidized low density lipoproteins. Some of these lipids rapidly enter cells to induce apoptosis by the intrinsic pathway, but how such lipids initiate this process is unknown. We show the truncated phospholipid hexadecyl azelaoyl glycerophosphocholine (Az-LPAF), derived from the fragmentation of abundant sn-2 linoleoyl residues, depolarized mitochondria of intact cells. Az-LPAF also depolarized isolated mitochondria and allowed NADH loss, but did not directly interfere with complex I function. Cyclosporin A blockade of the mitochondrial permeability transition pore partially prevented the loss of electrochemical potential. Depolarization of isolated mitochondria by the truncated phospholipid was readily reversed by the addition of albumin that sequestered this lipid. Ectopic expression of the anti-apoptotic protein Bcl-X(L) in HL-60 cells reduced apoptosis by the truncated phospholipid by protecting their mitochondria. Mitochondria isolated from these cells were also protected from Az-LPAF-induced depolarization. Conversely mitochondria isolated from Bid(-/-) animals that lack this pro-apoptotic Bcl-2 family member were resistant to Az-LPAF depolarization. Addition of recombinant full-length Bid, which has phospholipid transfer activity, restored this sensitivity. Thus, phospholipid oxidation products physically interact with mitochondria to continually depolarize this organelle without permanent harm, and Bcl-2 family members modulate this interaction with full-length Bid acting as a co-factor for pro-apoptotic, oxidatively truncated phospholipids.
authors: Department of Cell Biology, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors: Rui
authors: R
authors: Chen
authors: Ariel E
authors: AE
authors: Feldstein
authors: Thomas M
authors: TM
authors: McIntyre
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051023:BH3 Interacting Domain Death Agonist Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005434:Flow Cytometry; D018922:HL-60 Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D009243:NAD / Q000378:metabolism; D010084:Oxidation-Reduction; D010743:Phospholipids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D010743:Phospholipids; D051020:bcl-X Protein; D009243:NAD