Involvement of mitochondrial aerobic respiratory activity in efflux-mediated resistance of C. albicans to fluconazole

Abstract

Reduced intracellular accumulation of drugs mediated by efflux pump is one of the most critical mechanisms governing fluconazole (FLC) resistance in Candida albicans (C.albicans). Besides, mitochondrial aerobic respiration plays a major role in C.albicans metabolism. However, it is unclear whether mitochondrial aerobic respiration is involved with efflux-mediated resistance of C.albicans to azole. We measured key parameters of energy conversion, including the activity of respiratory chain complexes I, III and V (CI, CIII and CV), and reactive oxygen species (ROS) in two C.albicans strains (FLC-susceptible strain CA-1S and FLC-resistant strain CA-16R) obtained from a single parental source. Additionally, we quantified intracellular ATP levels and mitochondrial membrane potential (ΔΨm), which has critical effect on energy transport. Our analyses revealed a higher ATP level and ΔΨm in CA-16R compared with CA-1S (P<0.05), and a higher ATP level and ΔΨm in Sc5314S (FLC-susceptible strain) compared with Sc5314R (FLC-resistant strain). CI and CV activity increased in CA-16R, activity of CI, CIII and CV increased in Sc5314R. Additionally, ROS decreased in CA-16R and Sc5314R compared with their respective susceptible counterparts. Our data suggest that mitochondrial aerobic respiratory metabolism might be directly associated with the efflux-mediated resistance of C.albicans to azole. C.albicans strains might enhance the activity of efflux pumps and therefore decrease sensitivity to FLC through alteration of mitochondrial aerobic respiratory metabolism, by increased ATP production and decreased ROS generation.