L-2-hydroxyglutarate (L-2-HG), previously viewed as a toxic metabolic byproduct, acts as a signaling molecule that regulates gene expression and supports normal growth in mice. L-2-HG is normally kept at extremely low levels by L-2-HG dehydrogenase (L2HGDH), which converts it into 2-oxoglutarate. When this conversion fails in humans, L-2-HG accumulates and causes a rare neurological disorder, reinforcing the idea of toxicity. New findings reframe L-2-HG as part of regular physiology, including roles in kidney development. Mitochondria can influence gene responses through metabolism rather than serving only as an energy source.
"“This metabolite previously was described as a toxic metabolite, and not part of regular physiology,” said Chandel, who is also the David W. Cugell, MD, Professor of Medicine in the Division of Pulmonary and Critical Care and an investigator with the Chan Zuckerberg Initiative. “In this case, it's involved in kidney development, which we found.”"
"“For years, L‑2‑HG has been viewed primarily as a metabolic waste. In healthy cells, the molecule is kept at extremely low levels by an enzyme called L‑2‑HG dehydrogenase (L2HGDH), which converts it into another compound, 2‑oxoglutarate. When this process fails in humans, the resulting buildup of L-2-HG causes a rare neurological disorder.”"
"“We generally think everything is about your genes, right? You turn on a gene, you turn off a gene,” Chandel said. “And then there's metabolism, that's just for energy. What we found is that your mitochondria can also dictate those gene responses. It's just not a passive player.”"
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