The mitochondrial permeability transition pore in Ca²⁺ homeostasis

The mitochondrial Permeability Transition Pore (PTP) can be defined as a Ca²⁺ activated mega-channel involved in mitochondrial damage and cell death, making its inhibition a hallmark for therapeutic purposes in many PTP-related paradigms. Although long-lasting PTP openings have been widely studied, the physiological implications of transient openings (also called "flickering" behavior) are still poorly understood. The flickering activity was suggested to play a role in the regulation of Ca²⁺ and ROS homeostasis, and yet this hypothesis did not reach general consensus. This state of affairs might arise from the lack of unquestionable experimental evidence, due to limitations of the available techniques for capturing transient PTP activity and to a still partial understanding of its molecular identity. In this review we will focus on possible implications of the PTP in physiology, in particular its role as a Ca²⁺ release pathway, discussing the consequences of its forced inhibition. We will also consider the recent hypothesis of the existence of more permeability pathways and their potential involvement in mitochondrial physiology.