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

ABSTRACT: 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.

SUBMITTER: Wit N

PROVIDER: S-EPMC10191432 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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

Wit Niek N Gogola Ewa E West James A JA Vornbäumen Tristan T Seear Rachel V RV Bailey Peter S J PSJ Burgos-Barragan Guillermo G Wang Meng M Krawczyk Patrycja P Huberts Daphne H E W DHEW Gergely Fanni F Matheson Nicholas J NJ Kaser Arthur A Nathan James A JA Patel Ketan J KJ

Science advances 20230517 20

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. Me ...[more]

PMID: 37196082

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