Abstract
Ca2+-overload contributes to the oxidation of mitochondrial membrane lipids and associated events such as the permeability transition pore (MPTP) opening. Numerous experimental studies about the Ca2+/cardiolipin (CL) interaction are reported in the literature, but there are few studies in conjunction with theoretical approaches based on ab initio calculations. In the present study, the lipid fraction of the inner mitochondrial membrane was modeled as POPC/CL large unilamellar vesicles (LUVs). POPC/CL and, comparatively, POPC, and CL LUVs were challenged by singlet molecular oxygen using the anionic porphyrin TPPS4 as a photosensitizer and by free radicals produced by Fe2+-citrate. Calcium ion favored both types of lipid oxidation in a lipid composition-dependent manner. In membranes containing predominantly or exclusively POPC, Ca2+ increased the oxidation at later reaction times while the oxidation of CL membranes was exacerbated at the early times of reaction. Considering that Ca2+ interaction affects the lipid structure and packing, density functional theory (DFT) calculations were applied to the Ca2+ association with totally and partially protonated and deprotonated CL, in the presence of water. The interaction of totally and partially protonated CL head groups with Ca2+ decreased the intramolecular P-P distance and increased the hydrophobic volume of the acyl chains. Consistently with the theoretically predicted effect of Ca2+ on CL, in the absence of pro-oxidants, giant unilamellar vesicles (GUVs) challenged by Ca2+ formed buds and many internal vesicles. Therefore, Ca2+ induces changes in CL packing and increases the susceptibility of CL to the oxidation promoted by free radicals and excited species.
Highlights
Mitochondria are vital organelles for several metabolic processes involved in cellular function and dysfunction
Considering this premise, we modeled the lipid fraction of the inner mitochondrial membrane arranged as POPC (1-palmitoyl-2-oleoyl-sn-glycero3-phosphocholine)/tetraoleoyl cardiolipin (TOCL) large and giant unilamellar vesicles (LUVs and GUVs, respectively)
large unilamellar vesicles (LUVs) were challenged by the oxidative attack of excited species and free radicals simulating the events occurring in photodynamic therapy (PDT) and chemical oxidative stress promoted by the Fenton reaction
Summary
Mitochondria are vital organelles for several metabolic processes involved in cellular function and dysfunction. A well-known condition leading to the increase of superoxide production in mitochondria is the ischemia and reperfusion of tissues such as the myocardium and are events associated with the opening of the mitochondrial permeability transition pore (MPTP) (Kalogeris et al, 2014; Kim-Campbell et al, 2019; Menezes-Filho et al, 2019; Neginskaya et al, 2019; Sarkar et al, 2019). MPTP opens in Ca2+overloaded mitochondria leading to mitochondrial swelling and depolarization, inhibition of oxidative phosphorylation and stimulation of ATP hydrolysis (Zhao et al, 2004; Clarke et al, 2008; Giorgio et al, 2018; Vercesi et al, 2018; Xie et al, 2019). Experimental studies showed that the effects of Ca2+ on the CL-containing lipid bilayer organization increased its susceptibility to the oxidation by singlet oxygen and free radicals
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