Mitochondrial plasticity in cell fate regulation

Abstract

Edited by John M. Denu Mitochondria are considered highly plastic organelles. This plasticity enables the mitochondria to undergo morphological and functional changes in response to cellular demands. Stem cells also need to remain functionally plastic (i.e. to have the ability to "decide" whether to remain quiescent or to undergo activation upon signaling cues to support tissue function and homeostasis). Mitochondrial plasticity is thought to enable this reshaping of stem cell functions, integrating signaling cues with stem cell outcomes. Indeed, recent evidence highlights the crucial role of maintaining mitochondrial plasticity for stem cell biology. For example, tricarboxylic acid (TCA) cycle metabolites generated and metabolized in the mitochondria serve as cofactors for epigenetic enzymes, thereby coupling mitochondrial metabolism and transcriptional regulation. Another layer of mitochondrial plasticity has emerged, pointing toward mitochondrial dynamics in regulating stem cell fate decisions. Imposing imbalanced mitochondrial dynamics by manipulating the expression levels of the key molecular regulators of this process influences cellular outcomes by changing the nuclear transcriptional program. Moreover, reactive oxygen species have also been shown to play an important role in regulating transcriptional profiles in stem cells. In this review, we focus on recent findings demonstrating that mitochondria are essential regulators of stem cell activation and fate decisions. We also discuss the suggested mechanisms and alternative routes for mitochondria-to-nucleus communications. cro REVIEWS 13852 Figure 4. Metabolic control of histone acetylation levels. Metabolites and lipids implicated in the generation of Ac-CoA within the mitochondria and the nucleus of stem cells are depicted above. Note that enriched pathways depicted in blue will support the generation of cytosolic and nuclear pools of Ac-CoA and subsequent histone acetylation levels, whereas those depicted in red will repress the generation of cytosolic Ac-CoA and histone acetylation levels. Pathways shown in pink were reported to support bioenergetics of stem cells in response to the continuous citrate efflux. Blocking pyruvate entry into the mitochondria, allowing for nuclear-pyruvate accumulation together with active nuclear PDC, will support the generation of nuclear Ac-CoA pools. MPC, mitochondrial pyruvate carrier. JBC REVIEWS: Mitochondrial plasticity in cell fate regulation

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