Putative role of the calcium-dependent F1FO-ATPase activity in mitochondrial permeability transition

The mitochondrial F1FO-ATPsynthase/ase is a bi-powered enzymatic engine, skilled for massive ATP production by oxidative phosphorylation, but also able to operate in reverse by hydrolyzing ATP and acting as a proton pump to re-energize the membrane [1]. Universally known as the enzyme of life, recently this complex has also been defined as enzymatic switch between life and death, due to its implication with the mitochondrial permeability transition pore (MPTP), in turn involved in cell death [2]. Since Ca2+ is essential for MPTP opening, when its concentration rises in the matrix Ca2+ may replace the natural Mg2+ cofactor in the F1FO-ATPase activation. The Mg2+ and Ca2+-dependent F1FO-ATPase activities, already shown to be both oligomycin-sensitive [3], have a similar pH dependence. However pH differently modulates the enzyme inhibition by DCCD depending on the activating cation and NAD+ only inhibits the Ca2+ dependent F1FO-ATPase. The enzyme desensitization to oligomycin by thiol oxidation, both when either Ca2+ or Mg2+ activate the enzyme, shoulders the enzyme involvement in MPTP, reported as oligomycin-insensitive when specific Cys are oxidized [2]. Taken together the findings suggest that Ca2+-activated F1FO-ATPase may be functionally involved in the MPTP.