Mitochondrial permeability transition pore-dependent necrosis

Abstract

Mitochondrial permeability transition pore (mPTP)-dependent cell death is a form of necrotic cell death that is driven by mitochondrial dysfunction by the opening of the mPTP and is triggered by increases in matrix levels of Ca²⁺ and reactive oxygen species. This form of cell death has been implicated in ischemic injuries of the heart and brain as well as numerous degenerative diseases in the brain and skeletal muscle. This review focuses on the molecular triggers and regulators of mPTP-dependent necrosis in the context of myocardial ischemia reperfusion injury. Research over the past 50 years has led to the identity of regulators and putative pore-forming components of the mPTP. Finally, downstream consequences of activation of the mPTP as well as ongoing questions and areas of research are discussed. These questions pose a particular interest as targeting the mPTP could potentially represent an efficacious therapeutic strategy to reduce infarct size following an ischemic event.

Keywords: ANT; ATP synthase; BAK; BAX; Calcium; CypD; Ischemia reperfusion; MPTP; Mitochondria; Mitochondrial dysfunction; Necrosis; Permeability transition; ROS.

Figure 1:. Outstanding questions surrounding the regulation, identity, and pathological relevance of the mPTP.

Schematic representation of the current model of the mPTP, its regulators and its triggers. Though it is known that Ca²⁺ and ROS trigger the mPTP, and various protein components of the mPTP have been proposed, there are essential questions that remain to be addressed: ① How does Ca²⁺ trigger mPTP? ② How does ROS sensitize mPTP to Ca²⁺? ③ What is the target of CypD activity? ④ Is ANT a regulator or pore forming component of mPTP? ⑤ Is ATP synthase a regulator or pore forming component of mPTP? ⑥ How does outer mitochondrial membrane permeability influence matrix calcium retention capacity? ⑦ Are contact sites essential for mPTP activity? ⑧ Is the mPTP composed of two pore forming entities (ANT and ATP synthase pores)? ⑨ Are there additional pore forming components of the mPTP? ⑩ Can complete inhibition of mPTP protect humans against myocardial infarct injury?

Figure 2:. mPTP dependent mitochondrial dysfunction can potentially feed into other cell death pathways.

Following mPTP opening, mitochondrial membrane potential and eventually integrity decreases. This leads to a decrease in mitochondrial ATP production, which can lead to an increase in glycolysis as a compensatory mechanism to maintain the energetic demand of the cell. These events culminate in the reduction of the NAD+ pools which can sensitize a cell to parthanatos. Energetic depletion may also result in the over activation of autophagy, which may result in autophagic or lysosomal dependent cell death. In addition, mitochondrial membrane rupture can trigger other cell death modalities. For example, rupture can lead to Cytochrome C (Cyt C) release, which may initiate apoptosis or mtDNA release, which can initiate pyroptosis.