Mitochondria as intracellular signaling platforms in health and disease

Abstract

Mitochondria, long viewed solely in the context of bioenergetics, are increasingly emerging as critical hubs for intracellular signaling. Due to their bacterial origin, mitochondria possess their own genome and carry unique lipid components that endow these organelles with specialized properties to help orchestrate multiple signaling cascades. Mitochondrial signaling modulates diverse pathways ranging from metabolism to redox homeostasis to cell fate determination. Here, we review recent progress in our understanding of how mitochondria serve as intracellular signaling platforms with a particular emphasis on lipid-mediated signaling, innate immune activation, and retrograde signaling. We further discuss how these signaling properties might potentially be exploited to develop new therapeutic strategies for a range of age-related conditions.

Figure 1.

Lipid signaling in mitochondria. Mitochondrial cardiolipin and PE orchestrate multiple aspects of mitochondrial signaling and bioenergetics. These are summarized here diagrammatically. (1) Cardiolipin is synthesized from phosphatidylglycerol (PG) and remodeled at the IMM. (2) Cardiolipin acts as a ROS scavenger via oxidation and redox-mediated degradation. (3) Moderate levels of mitochondrial stress stimulates cardiolipin externalization. (4) Exposed cardiolipin can be recognized by LC3, stimulating mitophagic clearance. (5) Severe stress triggers cardiolipin-mediated cytochrome c release and apoptosis. (6) PE on the IMM is directly produced by the enzyme PISD, using PS synthesized on the ER and transported to mitochondria. (7) Stresses that inhibit mTORC1 rewires mitochondrial metabolism via a lipid signaling cascade, reducing PE levels on the IMM, leading to augmented YME1L activity, increased proteolysis and reduced mitochondrial biogenesis. DAG, diacylglycerol; mtCK, mitochondrial creatine kinase; tBID, truncated BH3-interacting domain death agonist. See text for additional details.

Figure 2.

Mitochondria at the crossroads of innate immune signaling and metabolism. Mitochondria are platforms for MAVS innate immune signaling that modulates mitochondrial function and integrates immunity with cellular metabolism. The various known intersections between MAVS and mitochondrial function are diagramed. (1) Cytosolic RNAs perceived as foreign activate MAVS aggregation via the RNA sensors MDA5 and RIG-I. (2) Mitochondrial MAVS aggregates activate signaling cascades, leading to transcriptional induction of type I IFNs and proinflammatory cytokines. (3) MAVS aggregation causes marked alterations in a range of mitochondrial functions. (4) MAVS signaling inhibits glycolysis by releasing HK2 from mitochondria; lactate, a metabolite of anaerobic glycolysis, in turn suppresses MAVS aggregation via direct binding. (5) Mitochondrial leakage of RNA and DNA causes inflammation through MAVS and STING pathways, respectively. (6) Feedforward mechanism exists between MAVS aggregation and mitochondrial ROS. (7) Deregulated sphingolipid metabolism activates MAVS signaling independently of RNA ligands. cPLA2, cytosolic phospholipase A2; G6P, glucose 6-phosphate; HK2, hexokinase 2.

Figure 3.

Mitochondrial retrograde signaling pathways. Three distinct modes of retrograde signaling that transform mitochondrial stress into nuclear programs are diagramed. On the left, mitochondrial protein folding stress is decoded into nuclear transcription via a lipid signaling-mediated UPR. In the center, mitochondrial stress provokes nuclear translocation of mitochondrial-tethered proteins or peptides that, in turn, initiate transcription of stress response genes. On the right, mitochondrial stresses, such as an increase in ROS levels, are translated into epigenetic modifications that facilitate transcriptional up-regulation of stress response genes. 6mA, N6-methyldeoxyadenine; AcH4K8, acetylation on histone H4 at lysine 8; H3K9me2, dimethylation at the ninth lysine residue of the histone H3 protein; MeH3K36, methylation on histone H3 at lysine 36.

Figure 4.

Therapeutic targeting of mitochondrial signaling. Strategies to target mitochondria include blocking mitochondrial damage by reducing mitochondrial ROS (antioxidants that are either broadly acting or mitochondrial specific), accelerating removal of damaged mitochondria by stimulating mitophagy (actinonin and urolithin A), and suppressing undesired inflammation caused by mitochondrial damage (inhibitors targeting the MAVS or cGAS–STING pathways). Metformin and the retrograde hormone MOTS-c appear to act through multiple mechanisms. mtROS, mitochondrial ROS.