A small-molecule DS44170716 inhibits Ca 2+ -induced mitochondrial permeability transition

Mitochondria are involved in a variety of physiological and pathological processes. Ca 2+ uptake is one of the important functions of the organelle for maintenance of cellular Ca 2+ homeostasis. In pathological conditions such as ischemia reperfusion injury, Ca 2+ overload into mitochondria induces mitochondrial permeability transition (MPT), a critical step for cell death. Because inhibition of MPT is a promising approach to protecting cells and organs, it is important for drug discovery to identify novel chemicals or mechanisms to inhibit MPT. Here we report upon a small-molecule compound DS44170716 that inhibits Ca 2+ -induced MPT in rat liver isolated mitochondria. DS44170716 protects human liver HepG2 cells from Ca 2+ -induced death with a level of protection similar to cyclosporin A (CsA). The inhibitory mechanism of DS44170716 against MPT is independent on PPIF, a target of CsA. DS44170716 blocks Ca 2+ flux into the mitochondria by decreasing mitochondrial membrane potential, while potently inhibiting mitochondrial complex III activities and weakly inhibiting complex IV and V activities. Similarly, complex III inhibitor antimycin A, complex IV inhibitor KCN or complex V inhibitor oligomycin inhibits Ca 2+ uptake of isolated mitochondria. These results show that DS44170716 is a novel class inhibitor of MPT by blocking of mitochondrial complexes and Ca 2+ -overload into mitochondria.