there are a number of mitochondrial

there are a number of mitochondrial processes that could be influenced by H2S during cold IRI. As previously described, low levels of H2S can stimulate ATP production through donation of electrons to the ETC (32). In the absence of O2 and nutrients during ischemia, this action of H2S could potentially minimize the detrimental impact of ATP depletion on cellular function and viability. Two recent studies by the same research group have shown that nM levels of AP39 can stimulate mitochondrial respiration and ATP production and are cytoprotective against oxidative stress in both endothelial and renal epithelial cells (35,36). The authors also showed that treatment of rats with AP39 during warm bilateral renal ischemia improved renal function and decreased oxidative stress and inflammation following reperfusion (36). These studies establish that stimulation of mitochondrial bioenergetics could be a viable protective mechanism through of H2S during cellular injury. However, another possibility is that H2S modulates mitochondrial ion channels during ischemic injury. It is well known that H2S can both activate and inhibit ion channel activity through persulfidation of various ion channel subunits (37). One recent study has shown that treatment of rats with AP39 can inhibit T-type Ca2+ channel activity on myocardial cell membranes (38), which could provide the basis for a similar effect on mitochondrial Ca2+ channels in our model. Considering the importance of mitochondrial Ca2+ influx and subsequent mitochondrial swelling in the pathogenesis of IRI, H2S potentially prevent MPTP formation during IRI via modulation of mitochondrial Ca2+ channel activity to pump out incoming Ca2+ ions or blunt initial Ca2+ influx. Due to its pleiotropic effects, the specific