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.
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