ABHD11 Enzyme Found to Repair Mitochondrial Energy Machinery in T Cells

Glutarate, a byproduct of lysine and tryptophan catabolism, can modify proteins through lysine glutarylation or conjugate to nonprotein substrates such as lipoic acid. While protein deglutarylation by SIRT5 was previously known, whether lipoyl glutarylation was reversible and biologically regulated remained unclear. This study identifies ABHD11 as the first enzyme capable of removing glutaryl adducts specifically from lipoate—a critical fatty acid cofactor covalently attached to five mitochondrial ketoacid dehydrogenase complexes that drive the TCA cycle.

Using the selective ABHD11 inhibitor ML226 and CRISPR-mediated gene depletion in HeLa cells, the authors demonstrated that ABHD11 loss rapidly reduces functional lipoylation—particularly on the E2 subunit of the 2-oxoglutarate dehydrogenase complex (OGDHc)—while simultaneously increasing glutaryl-lipoyl (Lpglu) adducts on the same sites. LC-MS/MS confirmed that OGDHc-E2 lysine K110 accumulated Lpglu modifications upon ABHD11 inhibition. OGDHc enzyme activity was impaired as a consequence, causing 2-oxoglutarate (2-OG) to accumulate intracellularly.

The downstream effects of 2-OG accumulation proved highly cell-type-specific. In cancer cell lines, elevated 2-OG inhibits HIF prolyl hydroxylase signaling and alters DNA methylation via 2-OG-dependent dioxygenases. By contrast, primary human CD8+ cytotoxic T lymphocytes—which express notably high ABHD11 levels—preserve 2-OGDD activity when ABHD11 is inhibited. Instead, impaired OGDHc function in these cells alters fatty acid metabolism and shifts differentiation, expanding the central memory T cell (TCM) pool. This suggests ABHD11 plays a meaningful role in T cell immunological programming.

Mechanistically, the study shows that glutaryl-lipoyl adducts form constitutively as a consequence of glutaryl-CoA metabolism in the mitochondria, and that ABHD11 continuously removes them to maintain TCA cycle integrity. This positions lipoyl glutarylation alongside canonical post-translational modifications as a dynamically regulated metabolic control mechanism. The broader implication is that TCA cycle enzymes are not simply passive catalysts but are actively tuned by reversible lipoyl modifications that respond to metabolic context.

These findings are relevant to diseases involving glutarate accumulation (such as glutaric aciduria type 1), mitochondrial dysfunction, and immune regulation. ABHD11 emerges as a potential therapeutic target for modulating T cell memory and metabolic reprogramming in immunity and disease.