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.
Highlights
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
Mitochondria have historically been viewed as bioenergetic and biosynthetic organelles; mitochondrial genetics has demonstrated that alterations in proteins that have similar effects on TCA cycle and electron transport chain (ETC) activity often yield divergent phenotypes, suggesting that mitochondrial perturbation must manifest beyond biosynthesis and bioenergetics
Signal transduction from mitochondria to the cytosol is referred to as retrograde signaling and signal transduction from cytosol to mitochondria as anterograde signaling, and the insights of the 1990s included those emerging from studies on anterograde signaling, most notably through cytosolic calcium entering into mitochondria to regulate bioenergetics [7]
Summary
There has been an explosion of scientific inquiry in the areas of mitochondrial genetics, cell biology and biochemistry [82]. Work in these fields is increasingly converging on the control of signaling events in the rest of the cell, with important implications for regulation of physiology and common diseases. Much has been deciphered about the types of signaling modes whereby mitochondria communicate with the rest of the cell, the molecular details remain sparse. A better understanding of the underlying mechanisms will hopefully yield insight into how to alleviate common diseases such as diabetes, cancer, and neurodegeneration, as well as provide insight into the early evolution of eukaryotes
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