Is mPTP the gatekeeper for necrosis, apoptosis, or both?

Abstract

Permeabilization of the mitochondrial membranes is a crucial step in apoptosis and necrosis. This phenomenon allows the release of mitochondrial death factors which trigger or facilitate different signaling cascades ultimately causing the execution of the cell. The mitochondrial permeability transition pore (mPTP) has long been known as one of the main regulators of mitochondria during cell death. mPTP opening can lead to matrix swelling, subsequent rupture of the outer membrane and a nonspecific release of intermembrane space proteins into the cytosol. While mPTP was purportedly associated with early apoptosis, recent observations suggest that mitochondrial permeabilization mediated by mPTP is generally more closely linked to events of late apoptosis and necrosis. Mechanisms of mitochondrial membrane permeabilization during cell death, involving three different mitochondrial channels, have been postulated. These include the mPTP in the inner membrane, and the mitochondrial apoptosis-induced channel (MAC) and voltage dependent anion-selective channel (VDAC) in the outer membrane. New developments on mPTP structure and function, and the involvement of mPTP, MAC, and VDAC in permeabilization of mitochondrial membranes during cell death are explored.

Phosphorylation of DYNLT1 at Serine 82 Regulates Microtubule Stability and Mitochondrial Permeabilization in Hypoxia

“…The complexes responsible for mPT pore activity span both the inner and outer membranes of mitochondria (Kinnally et al, 2011a). Opening of mPT pore can be triggered by several factors such as oxidative stress, mitochondrial membrane depolarization, etc.…”

Targeting Mitochondrial Function for the Treatment of Acute Spinal Cord Injury

“…As already mentioned, the mitochondrial inner membrane contains several intramembrane channels; opening of these channels is tightly regulated to prevent disruption of the mitochondrial inner membrane potential and ATP synthesis [19]. The mPTP is the most notorious of these channels, and opening of the mPTP has been linked to several different forms of cell death following SCI, including necrosis, apoptosis, autophagy, and necroptosis [19][20][21][22][23].…”

“…The mPTP is the most notorious of these channels, and opening of the mPTP has been linked to several different forms of cell death following SCI, including necrosis, apoptosis, autophagy, and necroptosis [19][20][21][22][23]. The molecular structure of the mPTP is still up for debate, but several lines of evidence previously suggested that VDAC in the mitochondrial outer membrane, adenine nucleotide translocator in the mitochondrial inner membrane, and cyclophilin D (Cyp-D) in the mitochondrial matrix were integral proteins that comprised the mPTP, at least in part [24][25][26].…”

“…High Ca 2+ levels are required when the inner membrane potential is strong, the matrix pH is low, or the ATP levels are high. Low Ca 2+ levels may open the mPTP when the levels of ATP are extremely low, the inner membrane potential is reduced, or the matrix level of ROS is high [19]. Once the mPTP opens, the mitochondrial inner membrane can no longer serve as a barrier against proton flow, leading not only to the release of Ca 2+ into the intermembrane space but also dissipation of the electrochemical gradient as the protons in the intermembrane space rush into the matrix, eventually causing a cessation of ATP synthesis [16].…”

Autophagy, Apoptosis, Mitoptosis and Necrosis: Interdependence Between Those Pathways and Effects on Cancer

“…Two partly interconnected apoptotic mechanisms exist; caspase-dependent classical apoptosis and caspase-independent programmed form of cell death, sometimes called necroptosis (Kinnally et al 2011;Smith and Yellon 2011). Both forms of cell death may be interconnected as caspases may lead to the activation of non-caspase proteases and vice versa.…”