Introduction to the Thematic Minireview Series: Redox metabolism and signaling

Abstract

In this sequel to the thematic collection of minireviews on redox metabolism and signaling published last year, five articles plumb the redox metabolic pathways relevant to cell proliferation, stress response and survival post-detachment from the extracellular matrix. The sixth article provides unexpected insights into the hepatic NAD(P)ome, revealing that more than half these proteins reside outside the cytoplasmic and mitochondrial compartments, pointing to the paucity of knowledge on their functions. Collectively, these articles highlight the metabolic adaptability of proliferating cells to meet redox needs, the use of lipids to mediate mitochondrial stress responses and the need for tools to interrogate compartment-specific pool sizes and oxidized/reduced ratios of antioxidants and lipids involved in redox homeostasis.In the first review (1), Hosios and Vander Heiden discuss the integration of redox cofactor requirements with metabolic activity needed to support mammalian cell proliferation. Biomass synthesis during cell proliferation requires redox equivalents to convert nutrients to lipids, proteins and nucleotides. The NAD + /NADH and NADP + /NADPH ratios are tightly regulated to serve their primary roles in nutrient oxidation and biosynthesis, respectively. Transamination reactions although redox neutral, link to the cellular redox status, interconverting the more oxidized keto to the less oxidized amino acid. One carbon metabolism connects amino acid, redox and nucleotide metabolism and are key to sustaining proliferation. This excellent overview of metabolism from a redox perspective, highlights the metabolic adaptability of proliferating cells to nutrient availability and growth conditions. In the second review (2), Kong and Chandel discuss mechanisms for regulating reactive oxygen species (ROS) in cancer and T cells, which interact in the context of antitumor immunity. The mitochondrial electron transfer chain and NADPH oxidases are the major sites of ROS generation. A host of factors including metabolic activity and cellular signaling pathways can activate ROS production while an army of antioxidant defenses, localized in all the major cellular compartments, counter ROS. Paradoxically, cancer cells exhibit expanded pro-and antioxidant capacity induced by mutations in oncogenes or tumor suppressors. The spatiotemporal control of pro-tumorigenic ROS signaling with concomitant protection of collateral oxidative damage of cellular targets is poorly understood. ROS signaling is also crucial for T cell activation and expansion as is an enhanced capacity to limit ROS-dependent damage at distal sites. The review concludes with a discussion of the therapeutic potential of antioxidants with spatial and temporal targeting in immune and/or cancer cells.In the third review (3), Goodman, Calvo and Mootha discuss challenges with studying the spatiotemporal compartmentalization of NAD(P)H metabolism. The paucity of information on compartment-specific pyridine nucleotide pool sizes and their oxidized/reduced ratios ...

Accelerating drug development for neuroblastoma: Summary of the Second Neuroblastoma Drug Development Strategy forum from Innovative Therapies for Children with Cancer and International Society of Paediatric Oncology Europe Neuroblastoma

“…In cancer cells, defects in the mitochondrial oxidative metabolism provide reduced equivalents through NADPH for metabolising hydroperoxides to increase production of superoxide, hydrogen peroxide and hydroperoxide [10]. The NADPH oxidases are an important site of ROS generation that is regulated in cancer cells and T cells in the context of antitumour immunity [11]. Several publications have highlighted the impact of NADPH on CM.…”