Mitochondria and cell signalling

Abstract

Mitochondria have long been considered as crucial organelles, primarily for their roles in biosynthetic reactions such as ATP synthesis. However, it is becoming increasingly apparent that mitochondria are intimately involved in cell signalling pathways. Mitochondria perform various signalling functions, serving as platforms to initiate cell signalling, as well as acting as transducers and effectors in multiple processes. Here, we discuss the active roles that mitochondria have in cell death signalling, innate immunity and autophagy. Common themes of mitochondrial regulation emerge from these diverse but interconnected processes. These include: the outer mitochondrial membrane serving as a major signalling platform, and regulation of cell signalling through mitochondrial dynamics and by mitochondrial metabolites, including ATP and reactive oxygen species. Importantly, defects in mitochondrial control of cell signalling and in the regulation of mitochondrial homeostasis might underpin many diseases, in particular age-related pathologies.

Fig. 1.

Mitochondrial regulation of apoptosis. Left: in the intrinsic pathway of apoptosis, pro-apoptotic stimuli such as DNA damage activate BH3-only proteins that, in turn, activate BAX and BAK. Active BAX and BAK cause mitochondrial outer membrane permeabilisation (MOMP), leading to release of proteins from the intermembrane space, including cytochrome c and SMAC (and Omi; not shown), which activate caspases and thereby cause apoptosis. MOMP can also lead to caspase-independent cell death. Right: in the extrinsic pathway, activation of cell surface death receptors leads to activation of the initiator caspase-8. In type II cells, mitochondria are required for apoptosis. Following death-receptor ligation, caspase-8 is activated at the OMM where it cleaves and activates the BH3-only protein BID, leading to BAX and BAK activation, leading to MOMP.

Fig. 2.

Mitochondria and antiviral signalling. Members of the RIG-I-like receptor (RLR) family, including RIG-I and MDA5, detect viral RNA, which causes their translocation to the OMM where they activate an adaptor protein called MAVS. MAVS undergoes oligomerisation, ultimately leading to upregulation of type I IFNs and pro-inflammatory cytokines. Positive regulators of MAVS activation include TOM70, STING and mitochondrial fusion, whereas negative regulators include NLRX1 and MFN2.

Fig. 3.

Mitochondrial ROS and innate immunity. Left: various PAMPs converge on the mitochondria, leading to upregulation of ROS. Mitochondrial ROS drive NLRP3 inflammasome activation, leading to caspase-1 activation that, in turn, cleaves and activates the pro-inflammatory cytokine IL-1β. Right: following activation, the Toll-like receptors TLR1, TLR2 and TLR4 activate TRAF6. TRAF6 translocates to the OMM and ubiquitinates ECSIT, leading to upregulation of mitochondrial ROS that have anti-microbial activity. MSU, monosodium urate, mtDNA, mitochondrial DNA.

Fig. 4.

Mitochondrial regulation of autophagy. Left: in yeast, loss of mitochondrial membrane potential leads to activation of PKA. PKA inhibits autophagy by repressing induction of ATG8 and by inhibiting ATG1–ATG13-induced autophagic flux. Centre: by regulating cellular ATP levels, mitochondria regulate autophagy through AMPK. When ATP levels are low, AMPK is activated and induces autophagy through direct phosphorylation of the ULK1–FIP200–ATG13 complex, and indirectly by inhibiting the suppression of autophagy by mTORC1. Ca²⁺ release by the ER enhances the tricarboxylic acid cycle (TCA cycle), upregulating ATP levels. Right: ammonia produced by mitochondrial-dependent glutaminolysis initiates autophagy by a non-conventional ULK1-independent mechanism. Under some conditions, the OMM can serve as a source of membrane for autophagosome biogenesis.

Fig. 5.

Parkin and NIX pathways of mitophagy. Top: in healthy mitochondria, the kinase PINK1 is imported into the mitochondrial intermembrane space and degraded in a manner dependent upon PARL protease. Following loss of mitochondrial transmembrane potential (Δψ_m), PINK1 fails to be imported into mitochondria and accumulates on the OMM, where it recruits Parkin. Parkin that localises to the mitochondria induces mitophagy, dependent upon its ubiquitin ligase activity. Bottom: during reticulocyte maturation, NIX is upregulated and localises to the mitochondria. At the mitochondria, NIX induces mitophagy, possibly through its ability to directly bind the autophagy protein LC3 and/or its ability to block BCL-XL inhibition of the key autophagy protein beclin-1.