Mitochondria in Cancer Stem Cells: From an Innocent Bystander to a Central Player in Therapy Resistance

Abstract

Cancer continues to rank among the world's leading causes of mortality despite advancements in treatment. Cancer stem cells, which can self-renew, are present in low abundance and contribute significantly to tumor recurrence, tumorigenicity, and drug resistance to various therapies. The drug resistance observed in cancer stem cells is attributed to several factors, such as cellular quiescence, dormancy, elevated aldehyde dehydrogenase activity, apoptosis evasion mechanisms, high expression of drug efflux pumps, protective vascular niche, enhanced DNA damage response, scavenging of reactive oxygen species, hypoxic stability, and stemness-related signaling pathways. Multiple studies have shown that mitochondria play a pivotal role in conferring drug resistance to cancer stem cells, through mitochondrial biogenesis, metabolism, and dynamics. A better understanding of how mitochondria contribute to tumorigenesis, heterogeneity, and drug resistance could lead to the development of innovative cancer treatments.

Keywords: cancer stem cells; drug resistance; metabolic dysfunction; mitochondria; therapy.

Figure 1

Mitochondrial Dysfunction and Cancer Stem Cells (CSCs). (a) Schematic of mitochondrial biogenesis and its regulation by transcription factors (PGC1, NRF, TFAM, PPAR, and ERR). Additionally, depicted are AMPK, oncogenic KRAS, and c-MYC-dependent mechanisms that lead to increase in biogenesis and energy production. This results in elevated oxidative phosphorylation (OXPHOS) and high ATP levels in CSCs. (b) Representation of mitochondrial metabolic dependency in CSCs. Cellular energy is derived through OXPHOS, fatty acid oxidation (FAO), and the TCA cycle within the mitochondria. CSCs exhibit increased oxidative phosphorylation for enhanced ATP production and elevated fatty acid oxidation through activation of oncogenic pathways. Deregulated TCA cycle enzymes in CSCs produce oncometabolites contributing to cancer progression. (c) Representation of altered mitochondrial dynamics in CSCs, where the balance between mitochondrial fission and fusion is disrupted. Upregulation of mitochondrial fission proteins (Drp1) and their regulators (Fis1, MID49, MID51, MFF) and downregulation of mitochondrial fusion proteins (Mfn1, Mfn2, OPA1) leads to impaired mitochondrial dynamics. (d) Increased activity of Ca²⁺-dependent kinases (PKC, CaN, CAMKIV, JNK, MAPK) due to altered membrane potential in CSCs is shown. Also indicated are the kinases and nuclear transcription factors involved in retrograde signaling. (e) Schematic representation of mitophagy in CSCs. Elevated cytoplasmic PINK1 phosphorylates Parkin and ubiquitinated-OMM proteins. Phosphorylated Parkin is transported into the mitochondria where it ubiquitinates itself and other mitochondrial substrates. These ubiquitin (Ub)-marked mitochondria are degraded by autophagosomes. (f) Mitochondria-mediated apoptosis in CSCs. Cells with damaged DNA activate caspase-8 mediated cell death. In CSCs, activation of caspase-8 is inhibited by high levels of c-FLIP; levels of pro-apoptotic proteins (Bax, Bak) are decreased while levels of anti-apoptotic proteins (Bcl-xL) are increased leading to cell survival and no apoptosis.