Mitochondria as multifaceted regulators of cell death

https://www.nature.com/articles/s41580-019-0173-8

Florian J. Bock, Stephen W. G. Tait

INTRODUCTION

It might look paradoxical that mitochondria are central to life as well as to cell death. However, programmed cell death is essential for health. The authors discuss the roles of mitochondria in cell death and their implications for health and disease. Here, I summarise the information about the involvement of mitochondria in apoptosis and other, recently described, forms of cell death.

1. The role of mitochondria is well established in apoptosis, where mitochondrial outer membrane permeabilization (MOMP) initiates a signalling cascade that leads to cell death. Recently, it has been appreciated that there are non-lethal functions of MOMP, triggering inflammation and immune response. See this blog post for more detail and a reference.
2. Necroptosis is a programmed form of cell death that shares morphological and inflammatory characteristics with necrosis, an unregulated and passive form of cell death due to disease, injury, or failure of the blood supply. Mitochondria are involved at least in some cell types: levels of ROS may be an important determinant as to whether a cell initiates necroptosis. Therefore, progressive mitochondrial dysfunction, like that observed during ageing, may increase the propensity of cells to undergo necroptosis. It has been observed, however, that necroptosis can proceed independently of mitochondria.
3. Pyroptosis is a highly inflammatory form of programmed cell death. It occurs most frequently upon infection with intracellular pathogens and is probably part of the antimicrobial response. There is little evidence that mitochondria play an important role in pyroptosis, but there is extensive crosstalk exists between pyroptosis and mitochondrial apoptosis.
4. Ferroptosis is a type of regulated cell death  triggered by lipid peroxides that kill the cell by attacking lipid membranes. It is dependent on iron (hence the name) and ROS (hence the mitochondrial involvement) in that lipid peroxides are produced through the Fenton reaction, requiring iron and peroxides.  Ferroptosis is characterized morphologically by morphological aberration of mitochondria.

Even though the role of mitochondria in 2-4 appears less crucial, or at least context dependent, these different cell death modalities crosstalk with one another and this crosstalk involves mitochondria.

Individual cristae within the same mitochondrion display different membrane potentials and are functionally independent

https://www.embopress.org/doi/10.15252/embj.2018101056

Dane M Wolf, Mayuko Segawa, Arun Kumar Kondadi, Ruchika Anand, Sean T Bailey, Andreas S Reichert, Alexander M van der Bliek, David B Shackelford, Marc Liesa, Orian S Shirihai

• It is often supposed that the inner mitochondrial membrane is at a uniform membrane potential (ΔΨm). 
• The authors develop an approach to evaluate ΔΨm at the level of individual cristae.
• The authors find the existence of heterogeneity in ΔΨm throughout the inner mitochondrial membrane, with individual cristae possessing different membrane potentials.
• Interventions causing acute depolarization to a particular crista may leave other cristae unchanged in their membrane potential.
• In other words, individual cristae seen to act as independent bioenergetic units, so that the failure of a specific one does not spread to the entire mitochondrion. Therefore, mitochondria should be thought of not as  electric wires, but as sets of batteries.
• The loss of this cristae compartmentalization, causing the spread of damage among regions of a mitochondrion, may be implied in pathological states. Several diseases are associated with structural perturbations in cristae. Restoring the heterogeneity of ΔΨm could represent a therapeutic avenue. 
• A fascinating area of future investigation would be to link cristae membrane heterogeneity to mitochondrial genetics.