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Summary: The plasticity of a preexisting regulatory circuit compromises the effectiveness of targeted therapies, and leveraging genetic vulnerabilities in cancer cells may overcome such adaptations. Hereditary leiomyomatosis renal cell carcinoma (HLRCC) is characterized by oxidative phosphorylation (OXPHOS) deficiency caused by fumarate hydratase (FH) nullizyogosity. To identify metabolic genes that are synthetically lethal with OXPHOS deficiency, we conducted a genetic loss-of-function screen and found that phosphogluconate dehydrogenase (PGD) inhibition robustly blocks the proliferation of FH mutant cancer cells both in vitro and in vivo. Mechanistically, PGD inhibition blocks glycolysis, suppresses reductive carboxylation of glutamine, and increases the NADP+/NADPH ratio to disrupt redox homeostasis. Furthermore, in the OXPHOS-proficient context, blocking OXPHOS using the small-molecule inhibitor IACS-010759 enhances sensitivity to PGD inhibition in vitro and in vivo. Together, our study reveals a dependency on PGD in OXPHOS-deficient tumors that might inform therapeutic intervention in specific patient populations. : Loss-of-function genetics screen reveals a synthetically lethal interaction between OXPHOS inhibition and phosphogluconate dehydrogenase (PGD) inactivation. Sun et al. provide an example of targeting tumor metabolism in a genetically predefined context to maximize therapeutic impact and propose PGD as a therapeutic target for fumarate hydratase-deficient HLRCC. Keywords: synthetic lethality, PGD, OXPHOS, tumor metabolism, metabolic vulnerability, fumarate hydratase, redox homeostasis, functional genomics, hereditary leiomyomatosis renal cell carcinoma, pentose phosphate pathway

Publisher Summary This chapter presents a review of the literature that suggests that increasing the antioxidant concentration, whether exogenously through the diet or through use of transgenic mouse models, is not sufficient to extend the life span of mice bred under optimal animal husbandry conditions. It suggests that the first premise of the free radical theory of aging, i.e., that an increase in antioxidants should extend life span, appears to be true only when short lived animal models are used, whether it is because they are genetically short-lived or because of suboptimal husbandry conditions. With regard to the second premise of the free radical theory of aging, that an increase in oxidants should shorten life span, the data accumulated so far leave little doubt that uncontrolled levels of reactive oxygen species are incompatible with mammalian life. The deleterious phenotypes of Sod2–/– and Gpx4–/– mice make this point very clearly. In addition, the increased levels of oxidative damage brought about by the absence of Sod1 are clearly sufficient to result in an increase in oxidative damage and a significant reduction in life span as well as to accelerate the course of several age-related pathologies. However, the effect of high levels of oxidative damage on aging is difficult to interpret because Sod1–/– mice also have a significant increase in cancer, which may contribute to the reduction in life span.

Publisher Summary This chapter presents an overview of Q-cycle bypass reactions at the Q 0 site of the cytochrome bc 1 and related complexes. The availability of high-resolution crystal structures, a large array of mutant strains in a number of species, and new spectroscopic approaches should greatly facilitate elucidation of the mechanisms by which the various bypass reactions are prevented. To aid this approach, this chapter describes the application and limitations of assays for detection of the various bypass reactions. A method is described for probing conformational changes in the ISP head domain, which are thought to be critical for preventing some of the bypass reactions. The chapter describes the Q-cycle and its bypass reactions. The chapter also elaborates about estimating the concentrations of cyt bc 1 and b6f complexes. The chapter presents the estimates of cyt bc 1 and b6f concentrations and measurements of the bifurcated oxidation of QH2 and probes the involvement of ISP domain movements in restricting bypass reactions. A simple method for estimating changes in the orientation and ordering of membrane-bound anisotropic EPR signals is also presented in the chapter.