Comparative effects of antimalarial drugs on oxidative phosphorylation, mitochondrial dynamics and mitophagy in...

Mitochondria occupy prominent position in cell metabolism. Information on changes in host mitochondrial capacity in electron transport system, dynamics and mitophagy in mice infected with resistant Plasmodium berghei and thereafter treated with some orthodox drugs, is critical to the survival and the organelles' metabolism. In this study, the effects of some antimalarial drugs were investigated on mitochondrial permeability transition (mPT) pore opening, F_oF₁ ATPase and lipid peroxidation, oxidative phosphorylation and mitochondrial dynamics in mice infected with chloroquine resistant (ANKA) strain of Plasmodium berghei. Thirty-five Swiss-mice (18 ± 3 g) were infected intraperitoneally with chloroquine resistant (ANKA) strain of Plasmodium berghei and treated orally and once daily with (10 mg/kg) dose of Amodiaquine artesunate (AA), Artemether-Lemefantrine (AL), Sulfadoxine- pyrimethamine (SP) and Artesunate (ART), On day 6, animals were sacrificed and livers were removed. Liver mitochondria were isolated and mitochondrial permeability transition (mPT) pore opening, F₀F₁ ATPase (mATPase) and lipid peroxidation (mLPO) were determined spectrophotometrically. Gene expressions on liver mitochondrial complexes I, II, III, IV and V, DNM1L, DRP1, OPA 1 Mitofusin 1 and 2, PINK 1, FUNDC1, PGC-1α and prohibitins 1 and 2 were determined using gel electrophoresis. AA, AL and SP did not significantly open the mPT pore while ART caused its opening (7 fold) and enhance mitochondrial F_oF₁ ATPase (P < 0.01), SP and AA induced peroxidation of mitochondrial membrane phospholipids (P < 0.01) when compared to the infected control. SP and AA significantly silenced the expressions of mitochondrial complexes. The effects of these drugs on mitochondrial fission and fusion vary significantly: AA down-regulated the expressions of DRP1, OPA 1 while AA, AL and ART decreased the expression of Mitofusin 2 as observed in the infected control. Significant down-regulation in the expressions of PINK 1 by SP, FUNDC1 by AA and AL, DNM1L by ART, PGC-1α by AA, AL, and ART, and prohibitins 1 and 2 by AA and AL similar to the infected control were observed. This study showed that host mitochondria respond differently to antimalarial drugs.