Physiological and pathological roles of the mitochondrial permeability transition pore in the heart

Abstract

Prolonged mitochondrial permeability transition pore (MPTP) opening results in mitochondrial energetic dysfunction, organelle swelling, rupture, and typically a type of necrotic cell death. However, acute opening of the MPTP has a critical physiologic role in regulating mitochondrial Ca(2+) handling and metabolism. Despite the physiological and pathological roles that the MPTP orchestrates, the proteins that comprise the pore itself remain an area of ongoing investigation. Here, we will discuss the molecular composition of the MPTP and its role in regulating cardiac physiology and disease. A better understanding of MPTP structure and function will likely suggest novel cardioprotective therapeutic approaches.

Figure 1

The molecular structure of the MPTP. The original paradigm of the MPTP featured VDAC, ANT and CypD as the core constituents of the complex (left). Genetic evaluation of putative MPTP components has shown that ANT, PiC, and CypD serve as pore regulators, while the BH3-domain pro-apoptotic proteins Bax/Bak function in the outer membrane to permit mitochondrial swelling and rupture once the inner membrane complex opens. The F₁F₀ ATP synthase has been suggested to be a candidate for the inner membrane pore forming unit of the MPTP (right). Abbreviations: IMM, inner mitochondrial membrane; OMM, outer mitochondrial membrane; IMS, intermembrane space.

Figure 2

Physiological and pathophysiological roles of the MPTP in the heart. Transient opening of the MPTP is implicated in ROS signaling, cardiomyocyte development and mitochondrial Ca²⁺ efflux that affects metabolism. Key components of the MPTP (PiC, ANT and the F₁F₀ ATP synthase) comprise the ATP synthasome thereby providing a direct link to mitochondrial energy metabolism. Prolonged MPTP opening leads to loss of mitochondrial membrane potential, cessation of ATP synthesis, mitochondrial swelling, rupture and death. Unregulated MPTP opening has been found to contribute to cardiac ischemia-reperfusion injury, and the development of heart failure. Abbreviations: Δψ, inner membrane potential.