Mitochondrial dynamics in cancer stem cells

Abstract

Many tumors are now understood to be heterogenous cell populations arising from a minority of epithelial-like cancer stem cells (CSCs). CSCs demonstrate distinctive metabolic signatures from the more differentiated surrounding tumor bulk that confer resistance to traditional chemotherapeutic regimens and potential for tumor relapse. Many CSC phenotypes including metabolism, epithelial-to-mesenchymal transition, cellular signaling pathway activity, and others, arise from altered mitochondrial function and turnover, which are regulated by constant cycles of mitochondrial fusion and fission. Further, recycling of mitochondria through mitophagy in CSCs is associated with maintenance of reactive oxygen species levels that dictate gene expression. The protein machinery that drives mitochondrial dynamics is surprisingly simple and may represent attractive new therapeutic avenues to target CSC metabolism and selectively eradicate tumor-generating cells to reduce the risks of metastasis and relapse for a variety of tumor types.

Keywords: Cancer stem cells; EMT; Metabolism; Mitochondrial dynamics; Mitochondrial morphology; Signaling; Therapeutic resistance.

Fig. 1

Mechanisms of mitochondrial dynamics-mediated EMT. a Myc upregulates expression of DRP1 and mitochondrial trafficking genes RHOT1 and TRAK2 by binding their promoter regions. Upregulation of these components increases mitochondrial motility to the cellular leading edge to promote focal adhesion complex (FAC) dynamics important for cellular migration, invasion, and metastasis [53]. b Depletion of mitochondrial DNA leads to mitochondrial fragmentation, which decreases mitochondrial calcium buffering. Increased cytosolic calcium activates calcineurin signaling to upregulate EMT gene expression [71]

Fig. 2

General phenotypes associated with mitochondrial fission or fusion in cancer stem cells (CSCs). Oncogenic signaling pathways affect mitochondrial dynamics and vice versa; for example, MAPK signaling increases mitochondrial fission whereas Myc has mixed effects. Mitochondrial fission is generally associated with increased rates of mitophagy, EMT, and glycolysis. Conversely, mitochondrial fusion is frequently associated with increased oxidative phosphorylation and therapeutic resistance