The mitochondrial permeability transition pore (mPTP) has been shown to play an important role in different pathologies, with particular relevance in cardiovascular diseases. Although different compounds and strategies have been shown to have cardioprotection in experimental models for ischaemia reperfusion injury, so far none of them was effective when translated to clinical practice. The poor clinical success is based in part on the fact that the molecular identity of the pore and its regulators is not completely understood. Additionally, most of the molecules tested have low bioavailability, with only a reduced percentage reaching mitochondria, preventing mPTP opening. The mitochondrial-targeting strategies should be a promising solution to increase the selectivity of compounds to the mPTP, reducing also their potential side effects. In this chapter we perform an integrative description of the effects of different mPTP inhibitors, that directly target one of the mPTP components, as well as developed strategies for desensitizing or inhibition of mPTP through indirect pathways. Moreover, strategies that inhibit mPTP opening by modulating mitochondrial calcium uptake, reactive oxygen species, and intracellular pH, as well as protocols of ischaemia and temperature preconditioning are also included. As a new perspective, we emphasize what should be clarified in the future in order to find potential cardioprotective strategies that may be successfully translated to clinical practice.
