Mechanistic connections between mitochondrial biology and regulated cell death

Mitochondrial regulation of ferroptosis

“…This electron transfer is coupled with proton pumping from mitochondrial matrix into the intermembrane space to establish proton motive force, which eventually drives ATP synthesis through complex V (ATP synthase). The mitochondrion is also the major organelle to produce reactive oxygen species (ROS) and hosts many other important metabolism processes, such as the tricarboxylic acid (TCA) cycle ( Friedman and Nunnari, 2014 ); in addition, mitochondria have vital roles in governing multiple forms of regulated cell death ( Chipuk et al, 2021 ).…”

“…Considering the central role of mitochondria in cell death regulation ( Chipuk et al, 2021 ; Green and Kroemer, 2004 ; Green and Reed, 1998 ; Li et al, 2004 ; Newmeyer and Ferguson-Miller, 2003 ) and the intimate link between ferroptosis and cellular metabolism ( Gao and Jiang, 2018 ; Gao et al, 2015 ; Gao et al, 2019 ; Lee et al, 2020 ; Stockwell et al, 2017 ; Zheng and Conrad, 2020 ), it has been postulated since the discovery of ferroptosis that the mitochondrion might also participate in governing ferroptosis. Indeed, the most notable morphological feature of ferroptotic cells under electron microscopy is the change in mitochondrial morphology; ferroptotic cells typically contain shrunken mitochondria with increased membrane density ( Dixon et al, 2012 ).…”

Role of Mitochondria in Radiation Responses: Epigenetic, Metabolic, and Signaling Impacts

“…Among the forms of regulated cell deaths, one can distinguish intrinsic apoptosis (mitochondria-driven, breakdown of mitochondria, condensation of nuclei, DNA cleavage apoptotic bodies), extrinsic apoptosis (membrane receptor-driven by death-inducing signaling complex involving also mitochondrial components such as MOMPs) and others such as mitochondrial membrane permeability transition (mitochondrial-driven transition pore (MTP)-necrosis (mitochondrial swelling and MOM rupture), ferroptosis (mitochondrial shrinkage, rupture, cristae disorder involving ROS), pyroptosis (condensation of chromatin, plasma membrane, permeabilization), parthanatos (PARP activation, DNA fragmentation, mitochondrial permeability, apoptosis-inducing factor (AIF) activation), entotic cell death (engulfment by non-phagocytic cells observed in neoplasia)), netotic cell death (membrane degradation involving NADPH oxidase-mediated ROS production, autophagy and release and translocation of granular enzymes from the cytosol to the nucleus), necrosis (cell swelling and rupture), necroptosis (necrotic membrane rupture, DAMP release), lysosome-dependent cell death (autophagy), autophagy-dependent cell death (autophagic cell death), alkaliptosis and oxytosis/oxeiptosis (necrotic mitochondrial shrinkage, rupture, cristae damage) and cellular senescence, mitotic catastrophe (failed mitosis, including giant cell formation, polyploidization and anaphase bridges) and immunogenic cell death [ 296 , 297 , 301 ].…”

“…Anoïkis results from the lack of cellular attachment to the extracellular matrix and involves mitochondrial functions of the intrinsic and extrinsic apoptotic pathways [ 306 ]. Inflammatory pyroptosis involves pattern receptor signaling, inflammasomes NLRP3 and NLRC4, caspase-1 ctivation, activation of gasdermin, plasma membrane pore formation and activation of the innate immune system via release of cytokines IL-1β and IL-18 [ 301 ]. Pyroptosis has some features in common with apoptosis [ 307 ] but is thought to be responsible for unwanted side effects and tissue toxicity observed after conventional RT [ 308 ].…”

Metabolic Control of Smoldering Neuroinflammation

“…Cellular metabolism is at the foundation of all biological activities (1). While the metabolic processes that support cellular bioenergetics and survival have been extensively studied (2,3), the role of metabolism in guiding complex cellular functions is yet to be completely understood. Extensive metabolic rewiring occurs in cells to adapt to the local microenvironment in physiological conditions (4), during development (5), and in conditions of disease (6), as cells try to preserve their functions under the shifting availability of energetic substrates.…”