Mechanistic connections between mitochondrial biology and regulated cell death

Abstract

The ancient, dynamic, and multifaceted functions of the mitochondrial network are essential for organismal homeostasis and contribute to numerous human diseases. As central hubs for metabolism, ion transport, and multiple macromolecular synthesis pathways, mitochondria establish and control extensive signaling networks to ensure cellular survival. In this review, we explore how these same mitochondrial functions also participate in the control of regulated cell death (RCD). We discuss the complementary essential mitochondrial functions as compartments that participate in the production and presentation of key molecules and platforms that actively enable, initiate, and execute RCD.

Keywords: cell biology; mitochondrial function; programed cell death; regulated cell death; signal transduction; stress signaling.

Figure 1.. Definitions of the mitochondrial compartments

A summary of the fundamental contributions of each mitochondrial compartment to mitochondrial biology and function. Abbreviations: ETC, electron transport chain; IMM, inner mitochondrial membrane; IMS, intermembrane space; mtDNA, mitochondrial DNA; OMM, outer mitochondrial membrane; OXPHOS, oxidative phosphorylation; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PI, phosphatidylinositol; PS, phosphatidylserine; TCA, tricarboxylic acid.

Figure 2.. Fundamental mitochondrial functions and pathways

(Upper left) Lipid composition of the mitochondrial membranes dictates organelle function. Major bilayer forming phospholipids (PC, PI, PS), along with additional lipid species (PE, CL), are differentially represented in the OMM and IMM (pie charts), and asymmetric between inner and outer leaflets of each membrane (histograms). The OMM/IMM contact site generates an additional unique lipid environment. Lipid composition and membrane contact sites contribute to overall membrane curvature. (Upper right) Structural and signaling lipids originate from the ER membrane (ERM; or other organelles—e.g., lysosomes) and are transferred to mitochondria where resident enzymes increase lipid diversity. Solid and dashed arrows denote reactions and transport, respectively. (Bottom left) Protein and ion import into mitochondria are mediated by a diverse system of specific carriers, enzymes, and chaperones, which deliver clients into the correct compartments. (Bottom right) Mitochondrial bioenergetics are based on the import of substrates into the mitochondrial matrix, which hosts several metabolic pathways (TCA cycle, beta-oxidation of fatty acids, and glutaminolysis) that provide essential cofactors to the ETC. Complexes I, III, and IV pump protons into the IMS, thus establishing Δψ_M for CV-mediated ATP generation. Oxygen radicals from the ETC may be scavenged by GSH to create GSSG and H₂O. Abbreviations: 2tH, 2-trans-hexadecenal; ADP/ATP, adenosine di-/tri-phosphate; C, citrate; CI–CV, complex I–V; Cer, ceramide; CL, cardiolipin; ETC, electron transport chain; F, fumarate; Glu, glutamate; GSH/GSSG, reduced/oxidized glutathione; IC, isocitrate; KG, α-ketoglutarate; M, malate; MCU, mitochondrial calcium uniporter; MFRN, mitoferrin; MIA, mitochondrial IMS assembly; MIM, mitochondrial import machinery 1-containing complex; MLCL, monolysocardiolipin; MPP, mitochondrial processing peptidase; O, oxaloacetate; OXA, oxidase assembly; OXPHOS, oxidative phosphorylation; PA, phosphatidic acid; PAM, presequence translocase-associated import motor; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PI, phosphatidylinositol; PS, phosphatidylserine; S, succinate; S1P, sphingosine-1-phosphate; SAM, sorting and assembly machinery; SC, succinyl-CoA; SM, sphingomyelin; Sph, sphingosine; sTIM, small TIM; TIM, translocase of the inner membrane; TOM, translocase of the outer membrane; VDAC, voltage-dependent anion channel.

Figure 3.. Multiple mitochondrial compartments control apoptosis via diverse mechanisms

Mitochondrial compartments (OMM, IMS, IMM, and matrix) maintain organelle function and homeostasis while harboring the potential to enable, initiate, and execute apoptosis. A brief summary of each mitochondrial compartment’s activities and/or signaling pathways that directly communicate to the apoptosis machinery are indicated. Detailed descriptions are provided in the text. Abbreviations: AIF, apoptosis-inducing factor; cyt c, cytochrome c; ETC, electron transport chain; ROS, reactive oxygen species; TCA, tricarboxylic acid; VDAC, voltage-dependent anion channel.