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

San Diego State University, San Diego CA

Investigators

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Abstract

ABSTRACT/SUMMARY Human isocitrate dehydrogenase 1 and 2 (IDH1, IDH2), which are highly conserved across many species, are responsible for the reversible NADP+-dependent oxidation of isocitrate (ICT) to α-ketoglutarate (αKG). Mutations in IDH have been implicated in > 80% of lower grade gliomas, 40% of chondrosarcomas, and ≤ 20% of acute myeloid leukemia cases. Though their conventional activity typically is ablated, IDH1 and IDH2 mutations confer a neomorphic activity: the NADPH-dependent production of oncometabolite D-2- hydroxyglutarate (D2HG). D2HG inhibits αKG-dependent enzymes like DNA and histone demethylases leading to epigenetic changes, and NADPH depletion can result in oxidative stress. The most common point mutations found in tumors are IDH1 R132H and IDH2 R140Q and R172K, though many other amino acid substitutions have been reported at these positions. Though much progress has been made in understanding the role of IDH in cancer, including the development of FDA-approved inhibitors, many key fundamental questions remain. We have recently shown that mutations in IDH1 have unique catalytic profiles, and we used a host of structural methods to elucidate mechanisms driving these kinetic differences. This work highlighted a surprising gap in our understanding of IDH – it is not yet clear which residues drive the chemistry of the neomorphic reaction. Here, we seek to determine the key features of disease-driving IDH1 and IDH2 mutants, including elucidating the interactions of wild type and mutant monomers upon dimerization to form the catalytic dimer, and the mechanisms of substrate binding and catalysis. A comprehensive understanding of kinetic and structural features of IDH1 and IDH2 mutants is important for elucidating the mechanistic features of dehydrogenases, a ubiquitous enzyme class. These discoveries can also serve to guide development of next generation inhibitors, and to help predict patient response to therapies. We also recently showed that unique IDH1 catalytic profiles can in turn alter D2HG levels in vitro and in vivo to affect tumor aggressiveness. Here, we return our focus to the most common mutations found in patients as we seek to determine the cellular consequences of IDH1 mutations beyond their role in altering DNA and histone methylation. Further, as IDH1 localizes to the cytosol and peroxisomes, this raises the possibility of organelle-specific effects of IDH1 mutations, which is an area that is underexplored. Identifying new pathways affected by IDH1 mutation allows us to better understand the roles wild type IDH1 plays to maintain healthy metabolism, as well as helps us to identify new pathways that may be ripe for therapeutic targeting. In our quest to establish the mechanisms of metabolic enzyme function in health and disease from the chemical to the in vivo levels by leveraging kinetic, structural, cellular, xenograft, and -omics technologies, we can establish the unique consequences of disease- relevant mutational variants in the most commonly mutated metabolic enzyme found in tumors.