L-2-hydroxyglutarate recycling is linked to coenzyme Q biosynthesis

Authors

Malatesta, M., Gottinger, A., Nicoll, C. R., Herebian, D., Mattiroli, D., Cecchini, D., Seibt, A., Alfieri, A., Distelmaier, F., Mattevi, A.

Abstract

The mitochondrial COQ metabolon catalyzes the late stages of the biosynthesis of coenzyme Q, an essential and ubiquitous cofactor. Here, by integrating coevolution, coexpression, colocalization and domain-fusion analyses, we identify L-2-hydroxyglutarate dehydrogenase (L2HGDH) as an integral component of this assembly. By acting in physical proximity to the COQ metabolon, L2HGDH sustains coenzyme Q production by maintaining the biosynthetic intermediates in their catalytically-active reduced state. Consistently, analysis of fibroblasts and urine samples from patients with primary coenzyme Q deficiency displayed marked accumulation of L-2-hydroxyglutarate. Cryo-electron microscopy reveals that L2HGDH forms a stable complex with COQ3 and COQ6, defining a heterotrimeric assembly that organizes catalytic sites on a shared membrane-facing surface thereby enabling localized quinone reduction. Together, these findings identify L2HGDH as a previously unrecognized component of the COQ metabolon, establish a direct link between central carbon metabolism and coenzyme Q biosynthesis, and expand the functional roles of metabolons in coordinating metabolic flux across distinct pathways.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 18 Jul 2026.

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