Mitochondrial metabolism and cancer

Abstract

Glycolysis has long been considered as the major metabolic process for energy production and anabolic growth in cancer cells. Although such a view has been instrumental for the development of powerful imaging tools that are still used in the clinics, it is now clear that mitochondria play a key role in oncogenesis. Besides exerting central bioenergetic functions, mitochondria provide indeed building blocks for tumor anabolism, control redox and calcium homeostasis, participate in transcriptional regulation, and govern cell death. Thus, mitochondria constitute promising targets for the development of novel anticancer agents. However, tumors arise, progress, and respond to therapy in the context of an intimate crosstalk with the host immune system, and many immunological functions rely on intact mitochondrial metabolism. Here, we review the cancer cell-intrinsic and cell-extrinsic mechanisms through which mitochondria influence all steps of oncogenesis, with a focus on the therapeutic potential of targeting mitochondrial metabolism for cancer therapy.

Figure 1

Mitochondrial metabolism in malignant transformation. Mitochondrial dysfunction can promote malignant transformation, i.e., the conversion of a healthy cell into a malignant precursor, as a consequence of (1) reactive oxygen species (ROS) overgeneration, which favors mutagenesis; (2) accumulation of succinate, fumarate or 2-hydroxyglutarate (all of which can operate as oncometabolites, at least in some settings); and/or (3) increased resistance to oncogene-driven mitochondrial outer membrane permeabilization (MOMP)- or mitochondrial permeability transition (MPT)-driven regulated cell death or cellular senescence.

Figure 2

Mitochondrial metabolism in tumor progression. Mitochondria influence multiple processes that underpin tumor progression, including the proliferation of transformed cells, their resistance to adverse microenvironmental conditions, their diversification, their interaction with the tumor stroma and their dissemination toward distant anatomical sites. In particular, (1) mitochondria are major sources of ATP and building blocks for the proliferation of malignant cells; (2) progressing cancer cells display an increased threshold for mitochondrial outer membrane permeabilization (MOMP) and mitochondrial permeability transition (MPT), which renders them less sensitive to harsh microenvironmental conditions; (3) slightly supraphysiological levels of mitochondrial reactive oxygen species (ROS) foster tumor diversification (herein represented with assorted plasma membrane colors) by favoring mutagenesis; (4) different subsets of malignant cells exhibit differential metabolic profiles, which are important for their survival and function; (5) the metastatic cascade relies on optimal mitochondrial biogenesis and oxidative phosphorylation (OXPHOS), at least at the initial dissemination step. However, imbalanced ROS overproduction consequent to severe mitochondrial dysfunction is generally incompatible with tumor progression, resulting in MOMP- or MPT-driven regulated cell death or cellular senescence.

Figure 3

Mitochondrial metabolism in response to treatment. All forms of treatment, including chemotherapy, radiation therapy and immunotherapy, aim at triggering the demise — via regulated cell death (RCD) — or permanent inactivation — via cellular senescence — of malignant cells (directly, or as a consequence of immunological mechanisms). Thus, mitochondria control therapy-driven RCD in cancer cells, implying that alterations in the molecular mechanism underpinning mitochondrial outer membrane permeabilization (MOMP) and mitochondrial permeability transition (MPT) are a major source of resistance. Moreover, mitochondrial ATP fuels several pumps of the ATP-binding cassette family, hence fostering chemoresistance upon the extrusion of xenobiotics from malignant cells. Finally, the ability of malignant cells to flexibly switch between glycolysis and oxidative phosphorylation appears to play a major role in multiple instances of resistance to oncogene inhibition.

Figure 4

Mitochondrial metabolism in immunosurveillance. Mitochondria are fundamental for the recognition of cancer cells by the immune system, as well as for the consequent activation of a tumor-targeting immune response. On the one hand, mitochondrial products including ATP, reactive oxygen species (ROS) and mitochondrial DNA (mtDNA) operate as danger signals, either extracellularly (like ATP) or intracellularly (like ROS and mtDNA). On the other hand, mitochondrial ROS are required for T-cell activation in response to TCR engagement, and oxidative phosphorylation (OXPHOS) is required for the establishment of immunological memory as well as for the tumoricidal and pro-inflammatory activity of M1 macrophages (MΦ). However, OXPHOS also supports the differentiation of immunosuppressive cells including M2 macrophages, CD4⁺CD25⁺FOXP3⁺ regulatory T (T_REG) cells and myeloid-derived suppressor cells (MDSCs). CTL, cytotoxic T lymphocyte.

Figure 5

Mitochondrial metabolism and oncogenesis. Mitochondria have a major impact on virtually all processes linked to oncogenesis, encompassing malignant transformation, tumor progression, response to treatment and anticancer immunosurveillance. C, cancer cell; D, dying cancer cell; L, lymphocyte; M, metastatic cancer cell; mtDNA, mitochondrial DNA; MOMP, mitochondrial outer membrane permeabilization; MPT, mitochondrial permeability transition; N, normal cell; OXPHOS, oxidative phosphorylation; R, resistant cancer cell; ROS, reactive oxygen species; TME, tumor microenvironment.