Mitochondria and cancer chemoresistance

Abstract

Mitochondria, known for more than a century as the energy powerhouse of a cell, represent key intracellular signaling hub that are emerging as important determinants of several aspects of cancer development and progression, including metabolic reprogramming, acquisition of metastatic capability, and response to chemotherapeutic drugs. The majority of cancer cells harbors somatic mutations in the mitochondrial genome (mtDNA) and/or alterations in the mtDNA content, leading to mitochondrial dysfunction. Decreased mtDNA content is also detected in tumor-initiating cells, a subpopulation of cancer cells that are believed to play an integral role in cancer recurrence following chemotherapy. Although mutations in mitochondrial genes are common in cancer cells, they do not shut down completely the mitochondrial energy metabolism and functionality. Instead, they promote rewiring of the bioenergetics and biosynthetic profile of a cancer cell through a mitochondria-to-nucleus signaling activated by "dysfunctional" mitochondria that results in changes in transcription and/or activity of cancer-related genes and signaling pathways. Different cancer cell types may undergo different bioenergetic changes, some to more glycolytic and some to more oxidative. These different metabolic signatures may coexist within the same tumor mass (intra-tumor heterogeneity). In this review we describe the current understanding of mitochondrial dysfunction in the context of cancer chemoresistance with special attention to the role of mtDNA alterations. We put emphasis on potential therapeutic strategies targeting different metabolic events specific to cancer cells, including glycolysis, glutaminolysis, oxidative phosphorylation, and the retrograde signaling, to prevent chemoresistance. We also highlight novel genome-editing strategies aimed at "correcting" mtDNA defects in cancer cells. We conclude on the importance of considering intratumor metabolic heterogeneity to develop effective metabolism-based cancer therapy that can overcome chemoresistance. This article is part of a Special Issue entitled Mitochondria in Cancer, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux.

FRK plays an oncogenic role in non‐small cell lung cancer by enhancing the stemness phenotype via induction of metabolic reprogramming

“…Metabolic reprogramming is a critical hallmark in malignant tumors and is involved in tumor proliferation and metastasis. Although the Warburg effect is widely considered as an important feature of metabolic reprogramming, other factors such as abnormal mitochondrial metabolism have also been shown to play important roles in tumor initiation and metastasis . These different metabolic signatures might coexist within the same tumor mass (intratumor heterogeneity).…”

“…Although the Warburg effect is widely considered as an important feature of metabolic reprogramming, other factors such as abnormal mitochondrial metabolism have also been shown to play important roles in tumor initiation and metastasis. 30 These different metabolic signatures might coexist within the same tumor mass (intratumor heterogeneity). Src activation could contribute to the Warburg effect in tumors by inhibiting pyruvate dehydrogenase through tyrosine phosphorylation.…”

Intercellular Communication in Tumor Biology: A Role for Mitochondrial Transfer

“…Mutations in mtDNA, changes in mtDNA copy number and epigenetic changes to mtDNA affecting mtDNA gene expression, are very common in a large variety of different types of cancer (21) leading to a re-balancing of mitochondrial and glycolytic energy metabolism to favor glycolysis. Highly glycolytic phenotypes have been associated with increased invasive and metastatic potential and chemoresistance to cancer treatments [reviewed by Guerra et al (22)]. In most instances cells with mutated mtDNA or reduced mtDNA copy number retain some level of functional mitochondrial electron transport.…”

“…In contrast, cells with mutated mtDNA or decreased mtDNA copy number have reduced ability to use the electron transport chain and may rely on glycolytic energy production, but they are still able to synthesize pyrimidines and thus are able to form tumors in vivo . Some authors (22) have attributed slower tumor development of injected ρ 0 tumor cells to their slower growth rate in vitro . However, most of these studies have not checked the ρ 0 tumors for the presence of mtDNA or respiration recovery.…”

Genomic heterogeneity meets cellular energetics: crosstalk between the mitochondria and the cell cycle

“…Dysfunctions in many of these mitochondrial processes have been associated with cancer development [40,42] and chemoresistance [43] . Similar to nuclear genomic heterogeneity, metabolic heterogeneity is also widespread in tumors.…”