2. Academic Validation
  3. Citrate metabolism controls the senescent microenvironment via the remodeling of pro-inflammatory enhancers

Citrate metabolism controls the senescent microenvironment via the remodeling of pro-inflammatory enhancers

  • Cell Rep. 2024 Aug 27;43(8):114496. doi: 10.1016/j.celrep.2024.114496.
Kan Etoh 1,  Hirotaka Araki 1,  Tomoaki Koga 1,  Yuko Hino 1,  Kanji Kuribayashi 1,  Shinjiro Hino 1,  Mitsuyoshi Nakao 2
Affiliations

Affiliations

  • 1 Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan.
  • 2 Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan. Electronic address: mnakao@gpo.kumamoto-u.ac.jp.
PMID: 39043191 DOI: 10.1016/j.celrep.2024.114496
Abstract

The senescent microenvironment and aged cells per se contribute to tissue remodeling, chronic inflammation, and age-associated dysfunction. However, the metabolic and epigenomic Bases of the senescence-associated secretory phenotype (SASP) remain largely unknown. Here, we show that ATP-citrate lyase (ACLY), a key Enzyme in acetyl-coenzyme A (CoA) synthesis, is essential for the pro-inflammatory SASP, independent of persistent growth arrest in senescent cells. Citrate-derived acetyl-CoA facilitates the action of SASP gene enhancers. ACLY-dependent de novo enhancers augment the recruitment of the chromatin reader BRD4, which causes SASP activation. Consistently, specific inhibitions of the ACLY-BRD4 axis suppress the STAT1-mediated interferon response, creating the pro-inflammatory microenvironment in senescent cells and tissues. Our results demonstrate that ACLY-dependent citrate metabolism represents a selective target for controlling SASP designed to promote healthy aging.

Keywords

ACLY; CP: Cell biology; CP: Metabolism; H3K27 acetylation; SASP; acetyl-CoA; citrate metabolism; senescence; senostatics.

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