A molecule once thought to be a harmful metabolic byproduct may play a crucial role in early development and gene regulation, according to a new study published in Nature that challenges decades of biochemical assumptions. 

In the study, Northwestern Medicine investigators found that L‑2‑hydroxyglutarate (L‑2‑HG) — a compound previously associated with rare metabolic disorders — acts as a signaling molecule that helps regulate gene expression and supports normal growth in mice.  

The findings suggest that some metabolites once thought to be purely toxic may have crucial physiologic functions, said Navdeep Chandel, PhD, professor of Biochemistry and Molecular Genetics and senior author of the new study.  

“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. 

Because of this, scientists have largely treated L‑2‑HG as a harmful byproduct. But the new study reframes that narrative.  

“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.” 

To identify how L‑2‑HG functions, investigators mapped its interactions with proteins and discovered it targets a family of enzymes that regulate gene activity by modifying chromatin. 

In collaboration with the laboratory of Ali Shilatifard, PhD, the Robert Francis Furchgott Professor and chair of Biochemistry and Molecular Genetics and director of the Simpson Querrey Institute for Epigenetics, who was a co-author of the study, investigators found that L-2‑HG inhibits the KDM4 family of demethylases, increasing histone H3K9me3, a repressive histone mark that shuts down gene transcription at specific sites.  

“What it does is it shuts off transcription by hitting a particular H3K9 methylation mark,” said Ram P. Chakrabarty, PhD, a postdoctoral fellow in the Chandel lab, who was first author of the study.  

In mouse embryonic stem cells, higher L‑2‑HG levels dampened the activity of specific genes, confirming its role as a regulator of gene expression. 

“This is an example of a metabolite that we know has nothing to do with generating ATP,” Chandel said. “It is a metabolite that we now can say is there to communicate between the mitochondria and nucleus to determine cell fate.” 

Mice engineered to reduce L‑2‑HG levels during development showed impaired growth, higher mortality and kidney abnormalities, according to the study. 

“It’s a metabolite that signals and it controls physiology,” Chandel said. “Because if we just get rid of that metabolite, we get a distinct pathology in the kidney.” 

Further analysis revealed that low L‑2‑HG disrupted the silencing of retrotransposons — genetic elements that can trigger inflammation if activated. 

“If this metabolite is high, it keeps inflammation down. If this metabolite is low, it allows these retrotransposons to come,” he said. 

The findings link metabolism to the control of genomic elements not previously thought to be metabolically regulated, Chandel said. The study also highlights a broader shift in scientific thinking: metabolism is not just a support system for cellular function, but a driver of it. 

“This is probably one of our cleanest examples,” Chandel said. “This molecule is made, it does its job, then it goes away. And it’s necessary for kidney development specifically.” 

He added that the discovery opens up new research directions in which retrotransposons have been implicated, ranging from cancer to aging to immune function. It also raises the possibility that metabolism may play a broader role in regulating retrotransposons, a concept that remains largely unexplored. 

Additional Feinberg co-authors included Benjamin Singer, ’07 MD, ’10 GME, the Lawrence Hicks Professor of Pulmonary Medicine; Samuel Weinberg, ’19 MD, ’19 PhD, assistant professor of Pathology in the Division of Experimental Pathology; Yuki Aoi, PhD, assistant professor of Medicine and of Biochemistry and Molecular Genetics; Feng Yue, PhD, the Duane and Susan Burnham Professor of Molecular Medicine; Yongchao C. Ma, PhD, associate professor of Pediatrics; Marta Iwanaszko, PhD, research associate professor of Biochemistry and Molecular Genetics; Colleen Reczek, PhD, research assistant professor of Medicine in the Division of Pulmonary and Critical Care; Dongmei Wang, PhD, research assistant professor of Pathology; Peng Gao, PhD, research associate professor of Medicine in the Division of Pulmonary and Critical Care; SeungHye Han, MD, MPH, assistant professor of Medicine in the Division of Pulmonary and Critical Care; and Shawn Davidson, PhD, assistant professor of Medicine in the Division of Pulmonary and Critical Care. 

The study was supported by National Institutes of Health (NIH) grants: R01CA290678, P01HL071643, P01AG049665, R01HL149883, R01HL153122, P01HL154998, U19AI135964, U19AI181102, R50CA265372, R01AG077451, R01HL172859, P01HL169188 and T32HL076139.