Mitochondrial regulation of cell death

Mitochondria are multifaceted organelles exerting vital as well as lethal functions within eukaryotic cells. When fueled with substrates and oxygen, mitochondria govern metabolic pathways, regulate calcium fluxes and are deeply involved in redox homeostasis. In stress conditions, notably when calcium and redox balances are altered, mitochondria sense cellular damages and ultimately, can orchestrate some phylogenetically-conserved forms of cell death such as intrinsic apoptosis, parthanatos as well as mitochondrial permeability transition-mediated necrosis. In contrast, they do not influence other cell death modalities such as necroptosis and ferroptosis. The execution of these mitochondria-dependent lethal processes involves the expression of mitochondria or nucleus-encoded proteins such as BCL-2 family members, VDAC, ANT, cytochrome c, Smac/Diablo, as well as Omi/HtrA2. In addition, mitochondria can also influence the cell fate through fusion/fission of the mitochondrial network and mitophagy to eliminate damaged mitochondria. Here, we will review and discuss basic knowledge on the role of mitochondria in the complex regulation of cell death.