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Review
. 2018 Apr 13;145(8):dev143420.
doi: 10.1242/dev.143420.

The role of mitochondria in stem cell fate and aging

Hongbo Zhang  1   2 , Keir J Menzies  3 , Johan Auwerx  4
Affiliations
Review

The role of mitochondria in stem cell fate and aging

Hongbo Zhang et al. Development. .

Abstract

The importance of mitochondria in energy metabolism, signal transduction and aging in post-mitotic tissues has been well established. Recently, the crucial role of mitochondrial-linked signaling in stem cell function has come to light and the importance of mitochondria in mediating stem cell activity is becoming increasingly recognized. Despite the fact that many stem cells exhibit low mitochondrial content and a reliance on mitochondrial-independent glycolytic metabolism for energy, accumulating evidence has implicated the importance of mitochondrial function in stem cell activation, fate decisions and defense against senescence. In this Review, we discuss the recent advances that link mitochondrial metabolism, homeostasis, stress responses, and dynamics to stem cell function, particularly in the context of disease and aging. This Review will also highlight some recent progress in mitochondrial therapeutics that may present attractive strategies for improving stem cell function as a basis for regenerative medicine and healthy aging.

Keywords: Aging; Cell fate; Mitochondria; Stem cell.

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Conflict of interest statement

Competing interestsThe authors declare no competing or financial interests.

Figures

Fig. 1.
Fig. 1.
Mitochondrial influence on stem cell fate. Asymmetric division generates two daughter cells with different mitochondrial properties. The daughter cell that received a greater proportion of new mitochondria maintains its stem cell traits whereas the daughter cell that received more older mitochondria tends to differentiate. Other mitochondrial signaling mechanisms, such as ROS and mitochondrial dynamics, are also involved in the balance between stem cell self-renewal and commitment. Mitochondrial reduction and dysfunction can further lead to stem cell aging, which is typically characterized by a reduction in stem cell renewal and premature commitment.
Fig. 2.
Fig. 2.
Mitochondrial metabolism and epigenetic regulation in stem cells. Mitochondrial TCA cycle intermediate metabolites, such as acetyl-CoA, citrate and α-KG, can be transported to the cytosol and nucleus where they may potentially control stem cell fate via the epigenetic regulation of histones and DNA. Acetyl-CoA is a co-factor of lysine acetyltransferases (KATs), which reverse the activity of the NAD+-dependent sirtuins (SIRTs) by catalyzing the acetylation of histones and other proteins. α-KG is the substrate for both histone (JHDMs) and DNA (TETs) demethylases. Mitochondrial one-carbon (One-C) metabolism coupled with cytosolic folate and methionine (Met) cycles generates SAM, which serves as the co-factor of histone (HMTs) and DNA (DNMTs) methyltransferases. FFA, free fatty acid; NAM, nicotinamide; SAH, S-adenosylhomocysteine.
Fig. 3.
Fig. 3.
UPRmt and stem cell regulation. Mitochondrial electron transport chain proteins are encoded by both the nuclear (green) and mitochondrial (red) genomes. Mitonuclear protein imbalance and proteotoxic stress, mitochondrial dynamics, and mitogenesis can all lead to mitochondrial stress, which activates the mitochondrial unfolded protein response (UPRmt). Retrograde UPRmt signaling, through prohibitin 1 and 2 (PHB and PHB2) and/or c-Jun N-terminal protein kinase (JNK2) and the protein kinase RNA-activated (PKR)-activating transcription factor 4 (ATF4) pathway (Quiros et al., 2017) can specifically regulate nuclear gene expression to generate more chaperones and proteases to alleviate proteotoxic stress. UPRmt-induced gene expression changes also lead to stem cell proliferation and a delayed senescence response. Pathways with the question marks are speculative and require further experimental confirmation. Solid and dashed arrows indicate direct and indirect pathway/links, respectively. NR, nicotinamide riboside; NMN, nicotinamide mononucleotide.
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