Mitochondria as multifaceted regulators of cell death

Mitochondria — the several hundred organelles inside almost every animal cell-type (and which are almost always inherited from the mother, not the father) — are essential for life. Positioned at the heart of cellular metabolism, they play a key role in generating adenosine triphosphate [ATP; the molecule that carries energy within cells, is the main energy manufacturer of the cell, and an end-product of the processes of photophosphorylation (adding a phosphate group to a molecule using energy from light), cellular respiration, and fermentation) via oxidative phosphorylation (the process by which ATP is formed as a result of transfer of electrons from NADH or FADH2 to O2 by a series of electron carriers; this takes place in mitochondria and is the major source of ATP in all O2-requiring organisms). Besides their many core metabolic functions, mitochondria participate in a vast array of cellular processes, ranging from inflammation to regulation of stem cell generation [see attached Review].

In addition, mitochondria are often essential for cell death. Regulated cell death reinforces health (e.g. inhibition of cell death promotes cancer and autoimmunity, whereas ’too much cell death’ contributes to neurodegenerative diseases — including Parkinson disease, Alzheimer disease, amyotrophic lateral sclerosis, and Huntington disease). Consequently, considerable effort is now being focused on targeting mitochondria to “manipulate cell death” in patients with certain diseases. For example, recently developed anticancer drugs called “BH3-mimetics” sensitize cells to mitochondria-​dependent death — displaying potent anti-tumor activity. Participation of mitochondria in cell death has been unequivocally established in apoptosis (‘natural’ death of cells that occurs as a normal process of an organism’s growth or development). Whereas apoptosis is a major form of regulated cell death, it is by no means the only form. Other recently described types of regulated cell death include necroptosis, pyroptosis and ferroptosis; the importance, and the role, of mitochondria in these three processes are described in detail in this Review [see attached].

In addition to the authors [see attached Review] highlighting new insights into how mitochondria initiate apoptosis, they discuss the parallel role of mitochondria in eliciting pro-inflammatory (signals in the environment or body that ‘stimulate’ inflammation) signaling activity, which has important consequences for physiology. Taken together — with recent studies showing heterogeneity in mitochondrial outer-membrane permeabilization (MOMP) between mitochondria (that are located inside the same cell treated with pro-​apoptotic stimuli) — authors emphasize that mitochondrial permeabilization can exert various non-​lethal signaling functions. Finally, authors summarize the contribution of mitochondria as a central connection between/among the four distinct cell death modalities: apoptosis, necroptosis, ferroptosis, and pyroptosis.


Nat Rev Mol Cell Biol 19 Oct 2019; in press (ePub)

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