A histone deacetylase 3 and mitochondrial complex I axis regulates toxic formaldehyde production

Sci Adv. 2023 May 19;9(20):eadg2235. doi: 10.1126/sciadv.adg2235. Epub 2023 May 17.


Cells produce considerable genotoxic formaldehyde from an unknown source. We carry out a genome-wide CRISPR-Cas9 genetic screen in metabolically engineered HAP1 cells that are auxotrophic for formaldehyde to find this cellular source. We identify histone deacetylase 3 (HDAC3) as a regulator of cellular formaldehyde production. HDAC3 regulation requires deacetylase activity, and a secondary genetic screen identifies several components of mitochondrial complex I as mediators of this regulation. Metabolic profiling indicates that this unexpected mitochondrial requirement for formaldehyde detoxification is separate from energy generation. HDAC3 and complex I therefore control the abundance of a ubiquitous genotoxic metabolite.

MeSH terms

  • Histone Deacetylases* / genetics
  • Histone Deacetylases* / metabolism


  • histone deacetylase 3
  • Histone Deacetylases