A small-molecule DS44170716 inhibits Ca-induced mitochondrial permeability transition.

Mitochondria are involved in a variety of physiological and pathological processes. Ca uptake is one of the important functions of the organelle for maintenance of cellular Ca homeostasis. In pathological conditions such as ischemia reperfusion injury, Ca 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-induced MPT in rat liver isolated mitochondria. DS44170716 protects human liver HepG2 cells from Ca-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 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 uptake of isolated mitochondria. These results show that DS44170716 is a novel class inhibitor of MPT by blocking of mitochondrial complexes and Ca-overload into mitochondria.