Posted on May 15, 2019 at 4:00 PM
Cell death is an essential part of life. As cells become old or broken, they are cleared away and destroyed. Mitochondria help decide which cells are destroyed. Two types of cell death controlled by mitochondria are apoptosis and necrosis. Apoptosis is a highly regulated process used in a number of biological processes, including fetal development, mopping up damaged cells, and maintaining cell numbers. In contrast, necrosis is a form of cell injury resulting in the premature death of cells in living tissues. The type of cell death that occurs depends on the particular biological setting.
Apoptosis can be activated by both intrinsic and extrinsic pathways. In the intrinsic pathway, the cell kills itself because it senses stress, while in the extrinsic pathway, the cell kills itself because of signals from other cells. Mitochondria control the intrinsic pathway, releasing proteins such as cytochrome c in response to cell stresses such as heat, infection, oxygen deprivation (i.e., hypoxia), increased calcium and nutrient deprivation. Cytochrome c then activates caspase, one of the chief enzymes involved in destroying cells during apoptosis. Because certain diseases, such as cancer, involve a breakdown in normal apoptosis, mitochondria are thought to play a role in these diseases.
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For the Scientist: Mitochondria play central roles in the regulation of several forms of cell death, including apoptosis and necrosis. There are two main modes of apoptosis that occur through the extrinsic and intrinsic pathways. Mitochondria are involved in both modes with distinct functions.
In the extrinsic pathway, extracellular ligand binding to transmembrane death receptors results in formation of the death-inducing signaling complex (DISC), leading to caspase-8 activation. Activated caspase-8 can cleave and activate a downstream caspase cascade, including caspase-3, which targets several hundreds of substrates, resulting in apoptotic cell death.
Mitochondria play a more crucial role in intrinsic apoptosis than in extrinsic apoptosis. In the intrinsic pathway, signals such as DNA damage, intracellular Ca2+ overload and oxidative or endoplasmic reticulum (ER) stress stimulate opening of the mitochondrial outer membrane (i.e., mitochondrial outer membrane permeabilization or POMP). This leads to a subsequent release of proapoptotic factors normally residing in mitochondria. The pro-apoptotic factor cytochrome c, an essential electron transport chain (ETC) protein, can assemble with Apaf-1, pro-caspase-9 and dATP once it is released into the cytosol to trigger the caspase cascade by caspase-9 activation.
Apoptosis-inducing factor (AIF) is also released from mitochondria during apoptosis, but it is normally anchored close to complex I of the ETC. Outside the mitochondria, it can promote DNA fragmentation as a part of the caspase-independent type of apoptosis. As AIF is normally anchored, it requires truncation prior its release from mitochondria. Moreover, second mitochondria-derived activator of caspases (Smac) are released from the mitochondria to the cytosol during apoptosis. These proteins bind inhibitor of apoptosis-proteins (IAPs), leading to activation of caspases.
As mitochondrial proteins that activate effector caspases are released in both pathways, permeabilization of the outer mitochondrial membrane represents a critical checkpoint during apoptosis and is under the control of the Bcl-2 family of proteins. This protein family possesses both pro-apoptotic (effector (Bax, Bak), and BH3-only proteins (Bad, Bim, Bid, Bik, Noxa, Puma, HRK, BMF) and anti-apoptotic functions (Bcl-2, Bcl-XL, Mcl-1, A1, Bcl-B, Bcl-w). The pro-apoptotic Bax and Bak are pore-forming proteins that can promote the release of pro-apoptotic proteins from the mitochondria to the cytosol to trigger the caspase cascade. Mitochondrial Ca2+ uptake and oxidative stress can trigger opening of a high-conductance pore in the inner mitochondrial membrane, called the mitochondrial permeability transition pore. Opening of this pore is controlled by Ca2+ but can be influenced by ATP production and oxidative stress.
Mitochondria are the primary source for reactive oxygen species (ROS) generation, which is tightly linked to apoptosis. Excessive ROS production can lead to the oxidation of macromolecules such as cardiolipin, the anchor of cytochrome c, to facilitate cytochrome c release and trigger the caspase cascade. Multiple antioxidants have been shown to display protective effects against apoptosis.
Anoikis is a specific form of apoptosis accompanied by a sudden loss of metabolic functions. During anoikis, which is induced upon cell detachment from the extracellular matrix, cells undergo dramatic metabolic changes characterized by decreased glucose uptake, glycolytic flux, mitochondrial respiration and pentose phosphate pathway activity. While the ATP and NADPH concentrations are reduced, ROS production is significantly increased, suggesting the importance of mitochondrial ROS in the execution of anoikis.
In contrast with apoptosis, necrosis is a morphologically distinct form of cell death characterized by mitochondrial swelling, loss of Djm, and impaired oxidative phosphorylation (OXPHOS) and ATP generation, concomitant with the release of apoptogenic proteins from mitochondria. These events block apoptotic cell death due to energetic failure. Further, programmed necrosis, necroptosis, mediated by receptor interacting protein kinase-3 (RIPK3), which is the best-characterized form of regulated necrosis, is suggested to require mitochondrial ROS generation, which is dependent on mitochondrial permeability transition and involves cyclophilin D but is independent of Bax and Bak. While cells that have been depleted of mitochondria through artificial mitophagy are resistant to apoptosis, cells lacking the vast majority of their mitochondria remain still sensitive to undergoing necroptosis, suggesting that mitochondria or mitochondrial metabolism may likely not to be entirely critical for the execution of necroptosis.