Physiopathology of the Permeability Transition Pore: Molecular Mechanisms in Human Pathology

Abstract

<jats:p>Mitochondrial permeability transition (MPT) is the sudden loss in the permeability of the inner mitochondrial membrane (IMM) to low-molecular-weight solutes. Due to osmotic forces, MPT is paralleled by a massive influx of water into the mitochondrial matrix, eventually leading to the structural collapse of the organelle. Thus, MPT can initiate outer-mitochondrial-membrane permeabilization (MOMP), promoting the activation of the apoptotic caspase cascade and caspase-independent cell-death mechanisms. The induction of MPT is mostly dependent on mitochondrial reactive oxygen species (ROS) and Ca2+, but is also dependent on the metabolic stage of the affected cell and signaling events. Therefore, since its discovery in the late 1970s, the role of MPT in human pathology has been heavily investigated. Here, we summarize the most significant findings corroborating a role for MPT in the etiology of a spectrum of human diseases, including diseases characterized by acute or chronic loss of adult cells and those characterized by neoplastic initiation.</jats:p>

Regulation of Cell Death by Mitochondrial Transport Systems of Calcium and Bcl-2 Proteins

“…mPTP/mPTPC (mitochondrial permeability transition pore or mPTP complex): mPTP or mPTPC is considered as the main transport system for Ca 2+ efflux from mitochondria under pathophysiological conditions [ 2 , 3 , 12 , 31 , 32 , 128 , 129 , 130 , 131 , 132 , 133 , 134 ]. Although the mPTPC was initially described in swelling experiments using the fraction of isolated mitochondria and characterized as a non-selective channel that transports ionic and nonionic molecules as early as 1979 [ 110 ], the transport mechanism of this channel actually remains poorly understood.…”

“…The opening of mPTP is directly regulated by the concentration of free Ca 2+ , and triggered by mitochondrial Ca 2+ overload, allowing for rapid Ca 2+ release from mitochondria [ 3 , 13 , 32 , 70 , 132 , 156 , 173 ]. Obviously, Ca 2+ is the most important regulator and inductor of mPTP opening, regarding its numerous indirect roles in the regulation and modulation of the mPTP [ 130 , 131 , 132 , 174 ].…”

“…Direct protein–protein interactions between Bcl-2 proteins and proteins involved in mPTPC formation (ANT, ATP synthase, and VDAC) have been documented [ 32 , 255 , 261 ] ( Table 1 ). In particular, the pro-apoptotic Bcl-2 proteins Bax and Bak have been reported to interact directly with mPTPC [ 252 , 258 ].…”

“…BID has been characterized as the BH3 protein, which could cooperate with the mPTPC components and regulate necrosis [ 299 ]. Altogether, both mPTP-mediated necrosis and MOMP-induced apoptosis can be regulated by Bcl-2 proteins, and triggered by mitochondrial Ca 2+ overload; causing damage of IMM integrity with catastrophic consequences, particularly bioenergetic collapse by dissipation of the mitochondrial membrane potential ( Figure 3 ) [ 3 , 32 , 283 , 293 ].…”

“…In turn, this induces a collapse of the mitochondrial membrane potential, termination of oxidative phosphorylation processes, osmotic changes, mitochondrial swelling, and inner membrane remodeling. All of these processes culminate by mitochondrial outer membrane permeabilization (MOMP) and the release of cytochrome c; being both an inducer of apoptosis and modulator of other proapoptotic factors [ 2 , 12 , 31 , 32 ]. Whereas mostly associated with programmed cell death, a number of compounds trigger changes in Ca 2+ homeostasis and mPTP-induced apoptosis [ 2 , 9 , 29 ].…”