Mitochondria play an essential role in bioenergetics and cellular Ca[Formula: see text] handling. The mitochondrial permeability transition pore (mPTP) is a non-specific channel located in the inner mitochondrial membrane. Long-lasting openings of the pore allow the rapid passage of ions and large molecules, which can result in cell death. The mPTP also exhibits transient, low conductance openings that contribute to Ca[Formula: see text] homeostasis. Although many regulators of the pore have been identified, none of them uniquely governs the passage between the two operating modes, which thus probably relies on a still unidentified network of interactions. By developing a core computational model for mPTP opening under the control of mitochondrial voltage and Ca[Formula: see text], we uncovered the existence of a positive feedback loop leading to bistability. The characteristics of the two stable steady-states correspond to those of the two opening states. When inserted in a full model of Ca[Formula: see text] handling by mitochondria, our description of the pore reproduces observations in mitochondrial suspensions. Moreover, the model predicted the occurrence of hysteresis in the switching between the two modes, upon addition and removal of free Ca[Formula: see text] in the extra-mitochondrial medium. Stochastic simulations then confirmed that the pore can undergo transient openings resembling those observed in intact cells.