Fundamental understanding of the role of cellular reducing power in physiology and disease
Cellular reducing power, which is stored in pyridine nucleotide cofactors NAD(H) and its phosphorylated form NADP(H), drives more than 500 biochemical reactions, including ATP generation, biosynthesis of macromolecules, and redox homeostasis. Dysregulation of cellular reducing power has been linked to many diseases, including cancer. However, the underlying mechanisms of this dysregulation are not well understood.
Recently, we identified the oncogenic PI3K-Akt pathway as a critical regulator of the cellular reducing power through direct stimulation of NAD+ kinase (NADK) (Hoxhaj et al., Science 2019). NADK catalyzes the phosphorylation of NAD+ to NADP+, which is then used to generate NADPH. Despite its importance, the mechanistic regulation of NADK and its cellular and metabolic functions are grossly understudied. Furthermore, the role of NADK in normal tissues and in cancer cells remains poorly defined.
Our laboratory is interested in identifying new regulators of NADK function and cellular reducing power in cancer. We employ quantitative metabolomics, biochemistry, proteomics, and mouse models to obtain a holistic understanding of the regulation of cellular reducing power in physiology and disease. Elucidating the pathways that control cellular redox in cancer could reveal new liabilities that can be exploited for cancer therapies.