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 fulllength 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 cofactor for pro-apoptotic, oxidatively truncated phospholipids.

Chronic Alcohol Exposure Increases Circulating Bioactive Oxidized Phospholipids

“…These peroxidized phospholipids are markers of oxidative stress, but they themselves have only limited direct biologic effects. They are, however, precursors of other phospholipids that can fulfill pathologic roles, including the initiation of an inflammatory reaction (11) or cell death (14,15), and so we additionally hypothesized that biologically active agents such as these oxidative truncation products of phospholipid hydroperoxides would appear in the circulation of animals chronically ingesting ethanol.…”

“…Some phospholipids derived from further oxidation and/or fragmentation of these phospholipid hydroperoxides are biologically active because they interact with TLR4 (38), CD36 (39), or PAF (40) receptors, because they chemically derivatize proteins (41)(42)(43)(44), or because they enter cells and initiate the process of mitochondria-dependent apoptosis (14,15). The presence of these types of phospholipid oxidation products in the circulation will have systemic consequences that would extend the oxidative stress of ethanol exposure to distal organs.…”

“…Oxidatively truncated phospholipids also affect cellular homeostasis by reducing mitochondrial integrity and function (12,13). A common truncation product of HpODE residues esterified at the sn-2 position is an esterified sn-2 azelaoyl fragment, and this oxidatively truncated phospholipid is particularly mitotoxic and effectively initiates the intrinsic caspase cascade leading to apoptotic cell death (14,15). Should these types of oxidation products accumulate in the circulation, production of reactive oxygen species in one organ would lead to mitochondrial damage, loss of mitochondrial function, and eventually cell death in distal tissues.…”

Metabolic signature of electrosurgical liver dissection

“…Here, we demonstrate in cellular assays, that a typical synthetic representative of these phospholipids, namely hexadecyl-azealin phosphadidylcholine (HAzPC) impairs tissue remodelling and wound healing and triggers apoptosis in cellular models for myofibroblasts and cholangiocytes, two hepatic cell types centrally involved in tissue repair. Previous reports in other cellular systems have shown, that the proapoptotic properties of HAzPC are mediated through mitochrondrial damage and caspase activation [28,29]. While future mechanistic studies need to determine the exact molecular links to tissue remodelling and wound healing, the activities of caspases could be pharmacologically blocked and could thus represent potential targets for perioperative interventions in order to minimize the tissue damage triggered by ES.…”

Mitochondrial outer membrane permeabilization: a focus on the role of mitochondrial membrane structural organization

“…These pores vary in size which may reflect the expandable nature of the lipidic pore. Chen et al (2009) . The timing 'before' and 'after' refers to the time at which changes are observed relative to MOMP.…”