bims-meprid 2025-01-26 papers

Sci Adv. 2025 Jan 24. 11(4): eadq9301

Mitochondrial fatty acid oxidation regulates monocytic type I interferon signaling via histone acetylation.

Jing Wu, Komudi Singh, Vivian Shing, Anand Gupta, Brett C Arenberg, Rebecca D Huffstutler, Duck-Yeon Lee, Michael N Sack.

Although lipid-derived acetyl-coenzyme A (CoA) is a major carbon source for histone acetylation, the contribution of fatty acid β-oxidation (FAO) to this process remains poorly characterized. To investigate this, we generated mitochondrial acetyl-CoA acetyltransferase 1 (ACAT1, distal FAO enzyme) knockout macrophages. 13C-carbon tracing confirmed reduced FA-derived carbon incorporation into histone H3, and RNA sequencing identified diminished interferon-stimulated gene expression in the absence of ACAT1. Chromatin accessibility at the Stat1 locus was diminished in ACAT1-/- cells. Chromatin immunoprecipitation analysis demonstrated reduced acetyl-H3 binding to Stat1 promoter/enhancer regions, and increasing histone acetylation rescued Stat1 expression. Interferon-β release was blunted in ACAT1-/- and recovered by ACAT1 reconstitution. Furthermore, ACAT1-dependent histone acetylation required an intact acetylcarnitine shuttle. Last, obese subjects' monocytes exhibited increased ACAT1 and histone acetylation levels. Thus, our study identifies an intriguing link between FAO-mediated epigenetic control of type I interferon signaling and uncovers a potential mechanistic nexus between obesity and type I interferon signaling.

DOI: https://doi.org/10.1126/sciadv.adq9301

Dev Cell. 2025 Jan 17. pii: S1534-5807(25)00027-9. [Epub ahead of print]

Lactate shuttling links histone lactylation to adult hippocampal neurogenesis in mice.

Zhimin Li, Ziqi Liang, Huan Qi, Xing Luo, Min Wang, Zhuo Du, Weixiang Guo.

DOI: https://doi.org/10.1016/j.devcel.2025.01.007

Nat Cancer. 2025 Jan 17.

Selective deficiency of mitochondrial respiratory complex I subunits Ndufs4/6 causes tumor immunogenicity.

Jiaxin Liang, Tevis Vitale, Xixi Zhang, Thomas D Jackson, Deyang Yu, Mark Jedrychowski, Steve P Gygi, Hans R Widlund, Kai W Wucherpfennig, Pere Puigserver.

Cancer cells frequently rewire their metabolism to support proliferation and evade immune surveillance, but little is known about metabolic targets that could increase immune surveillance. Here we show a specific means of mitochondrial respiratory complex I (CI) inhibition that improves tumor immunogenicity and sensitivity to immune checkpoint blockade (ICB). Targeted genetic deletion of either Ndufs4 or Ndufs6, but not other CI subunits, induces an immune-dependent growth attenuation in melanoma and breast cancer models. We show that deletion of Ndufs4 induces expression of the major histocompatibility complex (MHC) class I co-activator Nlrc5 and antigen presentation machinery components, most notably H2-K1. This induction of MHC-related genes is driven by a pyruvate dehydrogenase-dependent accumulation of mitochondrial acetyl-CoA, which leads to an increase in histone H3K27 acetylation within the Nlrc5 and H2-K1 promoters. Taken together, this work shows that selective CI inhibition restricts tumor growth and that specific targeting of Ndufs4 or Ndufs6 increases T cell surveillance and ICB responsiveness.

DOI: https://doi.org/10.1038/s43018-024-00895-x