The antioxidant Trolox restores mitochondrial membrane potential and Ca2+-stimulated ATP production in human complex I deficiency

Malfunction of mitochondrial complex I caused by nuclear gene mutations causes early-onset neurodegenerative diseases. Previous work using cultured fibroblasts of complex-I-deficient patients revealed elevated levels of reactive oxygen species (ROS) and reductions in both total Ca 2+ content of the endoplasmic reticulum (ER Ca ) and bradykinin(Bk)-induced increases in cytosolic and mitochondrial free Ca 2+ ([Ca 2+ ] C ; [Ca 2+ ] M ) and ATP ([ATP] C ; [ATP] M ) concentration. Here, we determined the mitochondrial membrane potential (Δ ψ ) in patient skin fibroblasts and show significant correlations with cellular ROS levels and ER Ca , i.e., the less negative Δ ψ , the higher these levels and the lower ER Ca . Treatment with 6-hydroxy-2,5,7,8-tetramethylchromane-2-carboxylic acid (Trolox) normalized Δ ψ and Bk-induced increases in [Ca 2+ ] M and [ATP] M . These effects were accompanied by an increase in ER Ca and Bk-induced increase in [Ca 2+ ] C . Together, these results provide evidence for an integral role of increased ROS levels in complex I deficiency and point to the potential therapeutic value of antioxidant treatment.