Emerging evidence for targeting mitochondrial metabolic dysfunction in cancer therapy

Abstract

Mammalian cells use a complex network of redox-dependent processes necessary to maintain cellular integrity during oxidative metabolism, as well as to protect against and/or adapt to stress. The disruption of these redox-dependent processes, including those in the mitochondria, creates a cellular environment permissive for progression to a malignant phenotype and the development of resistance to commonly used anticancer agents. An extension of this paradigm is that when these mitochondrial functions are altered by the events leading to transformation and ensuing downstream metabolic processes, they can be used as molecular biomarkers or targets in the development of new therapeutic interventions to selectively kill and/or sensitize cancer versus normal cells. In this Review we propose that mitochondrial oxidative metabolism is altered in tumor cells, and the central theme of this dysregulation is electron transport chain activity, folate metabolism, NADH/NADPH metabolism, thiol-mediated detoxification pathways, and redox-active metal ion metabolism. It is proposed that specific subgroups of human malignancies display distinct mitochondrial transformative and/or tumor signatures that may benefit from agents that target these pathways.

Figure 1. The horse and cart model describes the relationship between mitochondrial metabolism, signal transduction, and gene expression in mammalian biology, as well as in degenerative diseases associated with aging and cancer.

(A) In healthy mammalian cells, the essential redox metabolic process occurring in the mitochondria and cytosol can be considered as the horse, and its related gene expression can be considered as the cart. In normal cells, oxidative metabolism and gene expression are tightly coupled via the nonequilibrium steady-state fluxes of reactive metabolic by-products and leaking electrons (e^–) carriers, such as superoxide (O₂^•–) and hydrogen peroxide (H₂O₂). The level of DNA damage that occurs in a healthy cell is partially mitigated by ongoing DNA repair processes. (B) When the nonequilibrium steady state is disrupted, ROS and reactive oxidative by-products produced by oxidative metabolism (the horse) can increase oxidative damage in the genome, which will lead to the gradual deterioration of gene expression (the cart). Accumulation of DNA damage leads to cellular senescence or cancer. (C) The deregulated oxidative metabolism in cancer cells produces genomic instability that will eventually drag the cart off the cliff, so to speak, to the valley of death.

Figure 2. Interface of NAD synthesis and hydroperoxide metabolism.

In the de novo synthesis pathway, l-tryptophan is converted to nicotinic acid mononucleotide (NAMN) in a series of eight steps. The initial, rate-limiting steps are catalyzed by tryptophan 2,3-dioxygenases (TDOs) and indolamine 2,3-dioxygenases (IDOs). The salvage pathway arm, controlled by the enzyme NAPRT, enters the pathway at this stage. NAMN is then enzymatically converted to NAD⁺ by nicotinamide mononucleotide adenylyltransferase (NMNAT) and NADS (nicotinamide adenine dinucleotide sythetase). Nicotinamide (NAM) is an NAD⁺ precursor generated by deacetylation and ADP-ribosylation reactions catalyzed by sirtuins (SIRTs), poly(ADP-ribose) polymerases (PARPs), mono-ADP ribosyltransferases (MARTs), and ADP-ribosyl cyclases such as CD38. NAM can also be synthesized by NR kinases (NRKs), which catalyze the phosphorylation of nicotinamide riboside (NR). Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the regeneration of nicotinamide mononucleotide (NMN) from NAM. NMN is then enzymatically converted into NAD⁺ by NMNAT. NADP⁺ is synthesized from NAD⁺ by NAD kinase (NADK). NADP⁺ can be reduced to NADPH by a variety of dehydrogenases. NADPH serves as a source of reducing equivalents for the glutathione system, consisting of GSH, GSSG, GPx, and GR, and the thioredoxin system, consisting of Trx_SH, Trx_S-S, Prx, and TrxR. The glutathione and thioredoxin systems participate in the detoxification of H₂O₂ and organic hydroperoxides (ROOH). Enzymatic reactions are color-coded to their metabolic pathway of origin: dark green, pentose phosphate pathway; orange, TCA cycle; fuchsia, one-carbon metabolism. G6PD, glucose-6-phosphate dehydrogenase; 6PDG, 6-phosphogluconate dehydrogenase; ME1, malic enzyme 1; 10-CHO-THF, 10-Formyltetrahydrofolate; GLUD, glutamate dehydrogenase; THF, tetrahydrofolate; CAT, catalase.