Cystine import and oxidative catabolism fuel vascular growth and repair via nutrient-responsive histone acetylation.

Maria-Kyriaki Drekolia, Janina Mettner, Daiyu Wang, Fredy Delgado Lagos, Christian Koch, Dennis Hecker, Jeanette Eresch, Yifang Mao, Marion Bähr, Dieter Weichenhan, Julio Cordero, Janina Wittig, Boran Zhang, Hanyu Cui, Xiaoming Li, James A Oo, Andreas Weigert, Mauro Siragusa, Stephan Klatt, Ingrid Fleming, Stefan Günther, Mario Looso, Ralf P Brandes, Harald F Langer, Andreas Papapetropoulos, Mahak Singhal, Marcel H Schulz, Christoph Plass, Joerg Heineke, Gergana Dobreva, Jiong Hu, Sofia-Iris Bibli

European Center for Angioscience, Department of Vascular Dysfunction, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Goethe University Frankfurt, Institute for Vascular Signalling, Centre for Molecular Medicine, Frankfurt, Germany.European Center for Angioscience, Department of Vascular Dysfunction, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Goethe University Frankfurt, Institute for Vascular Signalling, Centre for Molecular Medicine, Frankfurt, Germany. · pubmed

Paper

Abstract

Endothelial metabolism underpins tissue regeneration, health, and longevity. We uncover a nuclear oxidative catabolic pathway linking cystine to gene regulation. Cells preparing to proliferate upregulate the SLC7A11 transporter to import cystine, which is oxidatively catabolized by cystathionine-γ-lyase (CSE) in the nucleus. This generates acetyl units via pyruvate dehydrogenase, driving site-specific histone H3 acetylation and chromatin remodeling that sustain endothelial transcription and proliferation. Combined loss of SLC7A11 and CSE abolishes cystine oxidative and reductive metabolism and causes embryonic lethality, whereas single deletions reveal distinct effects. SLC7A11 deficiency triggers compensatory cysteine de novo biosynthesis, partially maintaining angiogenesis, while CSE deletion disrupts nuclear cystine oxidative catabolism, transcription, and vessel formation. Therapeutically, cystine supplementation promotes vascular repair in retinopathy of prematurity, myocardial infarction, and injury in aging. These findings establish the role of cystine nuclear oxidative catabolism as a fundamental metabolic axis coupling nutrient utilization to gene regulation, with implications for vascular regeneration.

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Research summary

The paper claims that cystine import and oxidative catabolism are crucial for endothelial gene regulation and vascular repair. This research is relevant as it explores metabolic pathways that could influence tissue regeneration and longevity, addressing fundamental mechanisms that may underlie aging and age-related vascular health.

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