Regulation of PDH via cysteine oxidation on DLAT
Abstract
Pyruvate dehydrogenase (PDH) complex is a key regulator of metabolism, controlling flux from glycolysis into the tricarboxylic acid (TCA) cycle. PDH is often dysregulated in metabolic diseases and cancer. We discover here that in addition to its well characterized regulation by phosphorylation, PDH activity is also regulated via inhibitory oxidation of three cysteines of the DLAT subunit - Cys488, Cys586 and Cys618. Oxidation of these cysteines increases under oxidative stress, and is highly prevalent in mouse and human tissues. This mechanism enables cells to efficiently fight oxidative stress. Under oxidative stress, cells execute a metabolic shift, blocking glycolytic flux into the TCA cycle to shunt glycolytic carbons toward the pentose phosphate pathway. This generates NADPH which cells use to detoxify H ₂ O ₂ and to reduce oxidized cysteines. We find that DLAT oxidation is required for cells to mount an effective antioxidant response. Mutations preventing DLAT oxidation render PDH resistant to oxidative inhibition, impair NADPH generation, reduce peroxide detoxification, and sensitize cells to oxidative damage and death. DLAT oxidation also drives a Warburg-like metabolic phenotype of increased glucose uptake, elevated lactate secretion, and reduced TCA cycle activity. Thus DLAT oxidation is a redox-sensing mechanism that regulates PDH activity and central carbon metabolism.
Related
- Hierarchical cysteine oxidation controls reversible amyloid formation in an ankyrin repeat protein
- Topoisomerase IIβ Kinase: A protein processed from HIV-1 envelope by cysteine proteases
- A thioester-thiol exchange reaction in Salmonella Invasion acyl carrier protein transfers the 4PP-bound acyl chain to a distal cysteine
- Allosteric covalent inhibition of cereblon through cryptic cysteine targeting
- Disulfide Crosslink Density is a Key Determinant in the Formation, Dynamics, and Maturation of Cysteine-rich Designer Biomolecular Condensates.
BibTeX
@article{garciacortizo2026regulation,
title = {{Regulation of PDH via cysteine oxidation on DLAT}},
author = {Fabiola Garcia-Cortizo and Tobias Weber and Hana Nůsková and Daniel Pfaff and Michael Büttner and Angela Wirth and Elisabeth Kliemank and Gernot Poschet and Marc Freichel and Thomas Fleming and Alba Sulaj and Peter Paul Nawroth and Julia Szendroedi and Aurelio A. Teleman},
journal = {Nature Communications},
year = {2026},
month = oct,
doi = {10.1038/s41467-026-78266-6},
url = {https://www.nature.com/articles/s41467-026-78266-6},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Regulation of PDH via cysteine oxidation on DLAT
AU - Fabiola Garcia-Cortizo
AU - Tobias Weber
AU - Hana Nůsková
AU - Daniel Pfaff
AU - Michael Büttner
AU - Angela Wirth
AU - Elisabeth Kliemank
AU - Gernot Poschet
AU - Marc Freichel
AU - Thomas Fleming
AU - Alba Sulaj
AU - Peter Paul Nawroth
AU - Julia Szendroedi
AU - Aurelio A. Teleman
PY - 2026
DA - 2026/10/14
JO - Nature Communications
DO - 10.1038/s41467-026-78266-6
UR - https://www.nature.com/articles/s41467-026-78266-6
AB - Pyruvate dehydrogenase (PDH) complex is a key regulator of metabolism, controlling flux from glycolysis into the tricarboxylic acid (TCA) cycle. PDH is often dysregulated in metabolic diseases and cancer. We discover here that in addition to its well characterized regulation by phosphorylation, PDH activity is also regulated via inhibitory oxidation of three cysteines of the DLAT subunit - Cys488, Cys586 and Cys618. Oxidation of these cysteines increases under oxidative stress, and is highly prevalent in mouse and human tissues. This mechanism enables cells to efficiently fight oxidative stress. Under oxidative stress, cells execute a metabolic shift, blocking glycolytic flux into the TCA cycle to shunt glycolytic carbons toward the pentose phosphate pathway. This generates NADPH which cells use to detoxify H ₂ O ₂ and to reduce oxidized cysteines. We find that DLAT oxidation is required for cells to mount an effective antioxidant response. Mutations preventing DLAT oxidation render PDH resistant to oxidative inhibition, impair NADPH generation, reduce peroxide detoxification, and sensitize cells to oxidative damage and death. DLAT oxidation also drives a Warburg-like metabolic phenotype of increased glucose uptake, elevated lactate secretion, and reduced TCA cycle activity. Thus DLAT oxidation is a redox-sensing mechanism that regulates PDH activity and central carbon metabolism.
SN - 2041-1723
ER -