Abstract
Despite the promise of cancer medicine, major challenges currently confronting the treatment of cancer patients include chemoresistance and recurrence. The existence of subpopulations of cancer cells, known as cancer stem cells (CSCs), contributes to the failure of cancer therapies and is associated with poor clinical outcomes. Of note, one of the recently characterized features of CSCs is augmented mitochondrial function. The cytoskeleton network is essential in regulating mitochondrial morphology and rearrangement, which are inextricably linked to its functions, such as oxidative phosphorylation (OXPHOS). The interaction between the cytoskeleton and mitochondria can enable CSCs to adapt to challenging conditions, such as a lack of energy sources, and to maintain their stemness. Cytoskeleton-mediated mitochondrial trafficking and relocating to the high energy requirement region are crucial steps in epithelial-to-mesenchymal transition (EMT). In addition, the cytoskeleton itself interplays with and blocks the voltage-dependent anion channel (VDAC) to directly regulate bioenergetics. In this review, we describe the regulation of cellular bioenergetics in CSCs, focusing on the cytoskeleton-mediated dynamic control of mitochondrial structure and function.
Highlights
Mitochondria orchestrate diverse fundamental cellular functions, including respiration, calcium homeostasis, reactive oxygen species generation, and programmed cell death [1,2,3,4]
In agreement with the concept of metabolic plasticity of cancer cells, JARID1Bhigh cells [8] revealed a prominent increase in oxygen consumption, resulting in upregulation and downregulation of genes involved in the electron transport chain (ETC) and glycolysis, respectively [1]
We showed that cancer stem cells (CSCs) express sarco/endoplasmic reticulum Ca2+ -ATPase to avoid apoptosis, which occurs after Ca2+ overload under glucose deprived conditions [140]
Summary
Mitochondria orchestrate diverse fundamental cellular functions, including respiration, calcium homeostasis, reactive oxygen species generation, and programmed cell death [1,2,3,4]. They have been implicated in multiple steps of tumor progression and maintenance of cancer stemness, and heterogeneity in the morphology and spatial distribution of these organelles in cancer is becoming a field of intense investigation [3,5]. We summarize previous studies providing evidence for the role of cytoskeletal components in regulating the mitochondrial structure, function, and bioenergetics in a CSC model system. An in-depth understanding of CSC behavior can provide insights into cancer biology that may improve clinical applications aimed at targeting the bioenergetics of CSCs for treating drug-resistant malignant tumors
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