Mitochondrial Membrane Permeabilization in Cell Death

Abstract

Irrespective of the morphological features of end-stage cell death (that may be apoptotic, necrotic, autophagic, or mitotic), mitochondrial membrane permeabilization (MMP) is frequently the decisive event that delimits the frontier between survival and death. Thus mitochondrial membranes constitute the battleground on which opposing signals combat to seal the cell's fate. Local players that determine the propensity to MMP include the pro- and antiapoptotic members of the Bcl-2 family, proteins from the mitochondrialpermeability transition pore complex, as well as a plethora of interacting partners including mitochondrial lipids. Intermediate metabolites, redox processes, sphingolipids, ion gradients, transcription factors, as well as kinases and phosphatases link lethal and vital signals emanating from distinct subcellular compartments to mitochondria. Thus mitochondria integrate a variety of proapoptotic signals. Once MMP has been induced, it causes the release of catabolic hydrolases and activators of such enzymes (including those of caspases) from mitochondria. These catabolic enzymes as well as the cessation of the bioenergetic and redox functions of mitochondria finally lead to cell death, meaning that mitochondria coordinate the late stage of cellular demise. Pathological cell death induced by ischemia/reperfusion, intoxication with xenobiotics, neurodegenerative diseases, or viral infection also relies on MMP as a critical event. The inhibition of MMP constitutes an important strategy for the pharmaceutical prevention of unwarranted cell death. Conversely, induction of MMP in tumor cells constitutes the goal of anticancer chemotherapy.

Methods for the assessment of mitochondrial membrane permeabilization in apoptosis

“…MMP represents a crucial check-point in the cascade of events leading to cell death, with far-reaching consequences for the pathophysiology of cell death, as well as for its pharmacological manipulation [7][8][9]. Thus, the meticulous investigation of the mechanisms of MMP is essential not only for a deeper comprehension of molecular biology phenomena, but also (and more importantly) to guide future therapeutical interventions.…”

“…Death-promoting stimuli originating from other subcellular compartments (e.g. the nucleus, lysosomes, the endoplasmic reticulum, or the cytosol) converge on mitochondria where they favor mitochondrial membrane permeabilization (MMP) [7][8][9]. Upon permeabilization of the mitochondrial outer membrane (OM), intermembrane space (IMS) proteins, that include caspase activators such as cytochrome c (Cyt c) [10], Omi/HtrA2 (Omi stress-regulated endoprotease/High temperature requirement protein A 2) [11,12] and Smac/DIABLO (second mitochondria-derived activator of caspase/direct IAP binding protein with a low pI) [13,14], as well as caspase-independent death effectors like apoptosis-inducing factor (AIF) [15,16] and endonuclease G (EndoG) [17], are released into the cytosol.…”

Reoxygenation Reverses Hypoxic Pulmonary Arterial Remodeling by Inducing Smooth Muscle Cell Apoptosis via Reactive Oxygen Species–Mediated Mitochondrial Dysfunction

“…Apart from the main site of the mitochondrial ROS production, mitochondria are also important targets for the damaging effects of ROS. Therefore, mitochondrial regulation in cell death has drawn much attention recently 51, 52, 53. Generally, large amounts of ROS could result in mitochondrial dysfunction, including mitochondrial permeability transition, inhibition of mitochondrial ATP production, and unbalance of Bcl‐2‐like survival factors and Bax‐like death factors of Bcl‐2 family proteins, which eventually trigger mitochondrial outer membrane permeabilization and give rise to the release of intermembrane proapoptosis factors 21.…”

Multiple Pathways to the Same End: Mechanisms of Myonuclear Apoptosis in Sarcopenia of Aging

“…MOMP is also thought to occur via opening of the mitochondrial permeability transition pore (mPTP) [38]. The exact nature of the mPTP is still unclear.…”

“…Opening of the mPTP causes a sudden increase in membrane permeability to solutes with molecular weight up to 1,500 Da. This results in dissipation of membrane potential, mitochondrial swelling, and rupture of the OMM, with subsequent release of mitochondrial apoptotic mediators [38]. …”