"Isocitrate dehydrogenase (IDH) mutations as drivers of organelle stress and dysfunction"

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ABSTRACT/SUMMARY The consequences of mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 in cancer are unusual. Though these mutations confer a loss of function of the normal activity of the NADP+-dependent conversion of isocitrate to α-ketoglutarate (αKG), mutant IDH is more of an oncogene than tumor suppressor, as a neomorphic activity is also conferred: the NADPH-dependent production of oncometabolite D-2-hydroxyglutarate (D2HG) from αKG. D2HG inhibits αKG-dependent enzymes like DNA and histone demethylases, and NADPH depletion results in oxidative stress. A variety of point mutations affecting residue R132 in IDH1 can grant these catalytic properties, causing prominent structural modifications that allow mutant IDH1 to be a bona fide drug target. Indeed, a se- lective allosteric mutant IDH1 inhibitor is now in the clinic. Both mutant and WT IDH1 localize to the cytosol and peroxisomes, while IDH2 is found in the mitochondria, raising the possibility of organelle-specific consequences of IDH mutations, though this has not yet been explored. Interestingly, there is a communication pipeline between the peroxisomes and mitochondria in that they share an interconnected role in lipid processing and mitigation of oxidative stress, though the role of IDH in this communication is not yet known. To date, several limitations have restricted the rigor of mutant IDH studies. First, the catalytic and inhibition profile for R132H IDH1 is extrapolated to other disease-relevant IDH1 mutants, though we show several mutants have very unique profiles. Second, the role of NADPH depletion, and thus oxidative stress, is often overlooked in favor of studying consequences of D2HG. Third, studies focus on the global/cytosolic contributions of mutant IDH1, ignoring its role of sole NADPH and αKG producer in this organelle. However, we report evidence of dysfunctional lipid biosynthetic pathways in the peroxisomes upon introduction of cellular IDH1 mutations. The overall goal of our research program is to determine the mechanisms of metabolic enzyme catalysis, regulation, inhibition, and cellular/orga- nellular function in health and disease, from the chemical to the cellular levels. By leveraging kinetic, structural, cellular, and -omics technologies, we can establish the unique consequences of disease-relevant mutational variants in metabolic enzymes. Here, we have identified critical questions to illuminate the role of mutant IDH1 in disease: 1) How do protein dynamics affect IDH1 catalysis and inhibition? 2) What are the effects of oxidative stress on IDH1 and IDH2? 3) What are the organelle-specific consequences of IDH1 mutations? 4) What are the roles of IDH1 mutations in organelle crosstalk? Through this work, we will uncover fundamental catalytic and regulatory strategies affecting WT and mutant IDH activity, determine the role of IDH1 in the peroxisomes and identify the unique consequences of mutation at this location, and establish the role of mutant IDH1 in facilitating peroxisomal/mitochondrial lipid biosynthesis and oxidative stress signalling. Upon completing this work we will generate valuable new tools, and identify pathways or mechansims that may be therapeutically targetable.