The Contextual Roles of Isocitrate Dehydrogenase-1 and Isocitrate Dehydrogenase-2 in Electron Transport Chain Complex III Deficiency

Inborn errors of metabolism provide excellent opportunities in translational research, because individual clinical cases can stimulate insights that lead to a deeper understanding of human metabolism and sometimes inform personalized patient care. Our clinical genetics team identified a female patient who presented at age 3 with recurrent episodes of metabolic decompensation involving hypoglycemia and hyperlactatemia, but for whom conventional testing could not identify the underlying molecular defect. Whole exome sequencing identified compound heterozygosity for novel, putatively pathogenic variants in the gene encoding Ubiquinol-Cytochrome C Reductase Core Protein II (UQCRC2), a nuclear-encoded subunit of electron transport chain complex III (ETCIII). Only a handful of UQCRC2-deficient patients have been described worldwide, and none have been subjected to a detailed metabolic analysis to understand the impact of defects in this protein. We used CRISPR-Cas9 gene editing to generate UQCRC2-deficient cells in order to model deficiency of this protein. Metabolomic profiling of the patient's plasma and UQCRC2 KO cell lines demonstrated strong overlap, including some abnormalities broadly characteristic of ETC defects and others that may be more specific for ETCIII defects. UQCRC2-deficient cells constitutively exhibit reductive glutamine metabolism catalyzed by reversible isoforms of isocitrate dehydrogenase (IDH1 and IDH2) and undergo rapid cell death when glucose becomes scarce. Reasoning that these cell lines could be used to address basic questions about the contextual roles of IDH1 and IDH2 in regulation of the reductive carboxylation pathway, they were used to create concomitant IDH1 and IDH2 knockout lines. Surprisingly, loss of either enzyme did not suppress cell growth or survival under nutrient-replete conditions. However, we identified differential effects on reductive metabolism and on cell survival under nutrient deprivation. Specifically, we find that IDH1 is primarily responsible for reductive glutamine metabolism in these models of ETCIII deficiency. When glucose and glutamine become scarce, IDH2 supports cell survival while IDH1 becomes detrimental. We speculate that chronic IDH1-dependent utilization of reducing equivalents limits cell survival under nutritional stress. These findings present the first report of a context where wild-type IDH1 activity is detrimental to cell survival.