OGDH

Homologous recombination (HR) deficiency enhances sensitivity to DNA damaging agents commonly used to treat cancer. In HR-proficient cancers, metabolic mechanisms driving response or resistance to DNA damaging agents remain unclear. Here we identified that depletion of alpha-ketoglutarate (αKG) sensitizes HR-proficient cells to DNA damaging agents by metabolic regulation of histone acetylation. αKG is required for the activity of αKG-dependent dioxygenases (αKGDDs), and prior work has shown that changes in αKGDD affect demethylases. Using a targeted CRISPR knockout library consisting of 64 αKGDDs, we discovered that Trimethyllysine Hydroxylase Epsilon (TMLHE), the first and rate-limiting enzyme in de novo carnitine synthesis, is necessary for proliferation of HR-proficient cells in the presence of DNA damaging agents. Unexpectedly, αKG-mediated TMLHE-dependent carnitine synthesis was required for histone acetylation, while histone methylation was affected but dispensable. The increase in histone acetylation via αKG-dependent carnitine synthesis promoted HR-mediated DNA repair through site- and substrate-specific histone acetylation. These data demonstrate for the first time that HR-proficiency is mediated through αKG directly influencing histone acetylation via carnitine synthesis and provide a metabolic avenue to induce HR-deficiency and sensitivity to DNA damaging agents.

Parapyruvate is a substance commonly found in commercial dietary supplements of calcium pyruvate (DSCP) that inhibits the α-ketoglutarate dehydrogenase complex (KGDHC) and has been shown to induce senescence in human Hs68 cells. However, it is unknown whether parapyruvate can induce neurodegeneration. In this study, the parapyruvate content in DSCP was converted to an equivalent dose for mice and administered to the C57BL/6JNarl mice at doses around the equivalent dose for 69 days, including 5, 50, and 500 mg/kg/day. The Morris water maze (MWM) task and the active avoidance test were conducted to assess the learning and memory ability in mice, and then brain tissues were collected for biochemical analyses. The results demonstrated that parapyruvate significantly impaired the learning and memory ability, decreased the KGDHC activity, and promoted the oxidative stress and acetylcholinesterase (AChE) activity in mice in a dose-dependent manner. Additionally, parapyruvate induced Tau and phosphorylated Tau (p-Tau) aggregation at dosages ≥5 mg/kg/day and increased the myelin basic protein (MBP) expression at a dosage of 500 mg/kg/day. These results suggest that the equivalent dose of parapyruvate can induce neurodegeneration in the C57BL/6JNarl mice.

Eradication of acute myeloid leukemia (AML) is therapeutically challenging; many patients succumb to AML despite initially responding to conventional treatments. Here, we showed that the imipridone ONC213 elicits potent antileukemia activity in a subset of AML cell lines and primary patient samples, particularly in leukemia stem cells, while producing negligible toxicity in normal hematopoietic cells. ONC213 suppressed mitochondrial respiration and elevated alpha-ketoglutarate by suppressing alpha-ketoglutarate dehydrogenase (α-KGDH) activity. Deletion of OGDH, which encodes α-KGDH, suppressed AML fitness and impaired oxidative phosphorylation, highlighting the key role for α-KGDH inhibition in ONC213-induced death. ONC213 treatment induced a unique mitochondrial stress response and suppressed de novo protein synthesis in AML cells. Additionally, ONC213 reduced translation of MCL-1, which contributed to ONC213-induced apoptosis. Importantly, a patient-derived xenograft from a relapsed AML patient was sensitivity to ONC213 in vivo. Collectively these findings support further development of ONC213 for treating AML.