Mitochondria as signaling organelles

Abstract

Almost 20 years ago, the discovery that mitochondrial release of cytochrome c initiates a cascade that leads to cell death brought about a wholesale change in how cell biologists think of mitochondria. Formerly viewed as sites of biosynthesis and bioenergy production, these double membrane organelles could now be thought of as regulators of signal transduction. Within a few years, multiple other mitochondria-centric signaling mechanisms have been proposed, including release of reactive oxygen species and the scaffolding of signaling complexes on the outer mitochondrial membrane. It has also been shown that mitochondrial dysfunction causes induction of stress responses, bolstering the idea that mitochondria communicate their fitness to the rest of the cell. In the past decade, multiple new modes of mitochondrial signaling have been discovered. These include the release of metabolites, mitochondrial motility and dynamics, and interaction with other organelles such as endoplasmic reticulum in regulating signaling. Collectively these studies have established that mitochondria-dependent signaling has diverse physiological and pathophysiological outcomes. This review is a brief account of recent work in mitochondria-dependent signaling in the historical framework of the early studies.

Figure 1

Three essential functions of mitochondria. Mitochondria have three distinct functions in the maintenance of homeostasis: bioenergetics, biosynthesis, and signaling.

Figure 2

Mitochondria regulate signaling. Mitochondria regulate signaling pathways through release of cytochrome c to invoke caspase-dependent cell death, release of reactive oxygen species (ROS) to induce gene expression, and the use their outer membranes as a scaffold for signaling complexes, notably immune responses and control of cell death.

Figure 3

Mitochondrial dysfunction induces stress responses or mitophagy. Loss of mitochondrial electron transport chain function and/or misfolded proteins in mitochondrial matrix induces expression of genes through decreases in mitochondrial membrane potential. Sustained loss of mitochondrial membrane potential can invoke mitophagy, a process to eliminate dysfunctional mitochondria.

Figure 4

Emerging modes of mitochondria-dependent signaling. Mitochondrial production of metabolites and mitochondrial dynamics (motility and fission/fusion) regulate signaling. Mitochondrial interaction with specific subdomains of the endoplasmic reticulum (ER), referred to as mitochondria-associated membranes or MAMs, are emerging as important regulators of signaling transduction.