Impact of Antioxidants on Cardiolipin Oxidation in Liposomes: Why Mitochondrial Cardiolipin Serves as an Apoptotic Signal?

Abstract

Molecules of mitochondrial cardiolipin (CL) get selectively oxidized upon oxidative stress, which triggers the intrinsic apoptotic pathway. In a chemical model most closely resembling the mitochondrial membrane—liposomes of pure bovine heart CL—we compared ubiquinol-10, ubiquinol-6, and alpha-tocopherol, the most widespread naturally occurring antioxidants, with man-made, quinol-based amphiphilic antioxidants. Lipid peroxidation was induced by addition of an azo initiator in the absence and presence of diverse antioxidants, respectively. The kinetics of CL oxidation was monitored via formation of conjugated dienes at 234 nm. We found that natural ubiquinols and ubiquinol-based amphiphilic antioxidants were equally efficient in protecting CL liposomes from peroxidation; the chromanol-based antioxidants, including alpha-tocopherol, were 2-3 times less efficient. Amphiphilic antioxidants, but not natural ubiquinols and alpha-tocopherol, were able, additionally, to protect the CL bilayer from oxidation by acting from the water phase. We suggest that the previously reported therapeutic efficiency of mitochondrially targeted amphiphilic antioxidants is owing to their ability to protect those CL molecules that are inaccessible to natural hydrophobic antioxidants, being trapped within respiratory supercomplexes. The high susceptibility of such occluded CL molecules to oxidation may have prompted their recruitment as apoptotic signaling molecules by nature.

Novel Fluorescent Mitochondria-Targeted Probe MitoCLox Reports Lipid Peroxidation in Response to Oxidative Stress In Vivo

“…Imidazole-substituted analogs of fatty acids that were conjugated with TPP + inhibited cytochrome c-dependent CL peroxidation and protected mouse embryonic cells exposed to ionizing irradiation [26]. As argued elsewhere, the protective and antiaging effects of mitochondria-targeted antioxidants with various cationic maieties could be due to the specific protection of CL against peroxidation [27,28].…”

Molecular dynamics modeling of the interaction of cationic fluorescent lipid peroxidation-sensitive probes with the mitochondrial membrane

“…В различных моделях окислительного стресса, а также в моделях различных патологий они оказались значительно более эффективны чем природные липофильные антиоксиданты -убихинол и α-токоферол [4]. Предполагается, что благодаря положительному заряду и амфифильности митохондриальнонаправленные антиоксиданты взаимодействуют с молекулами CL и предотвращают их окисление во внутренней мембране митохондрий [5].…”

The Combination of Physical Exercise with Muscle‐Directed Antioxidants to Counteract Sarcopenia: A Biomedical Rationale for Pleiotropic Treatment with Creatine and Coenzyme Q10

“…Peroxidation of bioactive lipids and phospholipids of the inner mitochondrial membrane can perpetuate a vicious circle by hampering the supramolecular organization of the respiratory supercomplex I 1 III 2 (SC) [ 34 ] thus favouring further generation of the superoxide anion radical by complex I, which eventually leads to catastrophic metabolic deficiency of mitochondria. One of the first signals in mitochondria is oxidized cardiolipin (CL) [ 35 ]. Bound CL molecules are seen in the crystal structures of the respiratory complexes and have been recently shown to stabilize, indeed, the respiratory supercomplexes.…”