Perspectives on formaldehyde dysregulation: Mitochondrial DNA damage and repair in mammalian cells

Abstract

Maintaining genome stability involves coordination between different subcellular compartments providing cells with DNA repair systems that safeguard against environmental and endogenous stresses. Organisms produce the chemically reactive molecule formaldehyde as a component of one-carbon metabolism, and cells maintain systems to regulate endogenous levels of formaldehyde under physiological conditions, preventing genotoxicity, among other adverse effects. Dysregulation of formaldehyde is associated with several diseases, including cancer and neurodegenerative disorders. In the present review, we discuss the complex topic of endogenous formaldehyde metabolism and summarize advances in research on fo dysregulation, along with future research perspectives.

Keywords: DNA damage; Formaldehyde; Mitochondrial DNA; One carbon metabolism.

Fig. 1.

Endogenous sources of formaldehyde. Scheme showing key metabolic processes that generate formaldehyde in mammalian cells.

Fig. 2.

Demethylation of histones produces formaldehyde. A) Lysine specific demethylase (LSD1) and B) Jumonji C (JmjC) domain removal of methyl groups from lysine (Lys) residues in histones. Reactions in both A and B release formaldehyde.

Fig. 3.

Simplified scheme illustrating formaldehyde reactions involved in canonical one-carbon metabolism. Distinct cytoplasmic and mitochondrial one-carbon metabolism reactions enable eukaryotic cells to support biochemical processes, such as nucleotide, amino acid and methyl group biosynthesis, essential for survival and DNA metabolism. The figure was adapted from reference .

Fig. 4.

Catabolism of formaldehyde. Scheme showing key clearance systems to prevent accumulation of formaldehyde in mammalian cells.

Fig. 5.

Summary of formaldehyde-induced DNA damage and repair. Endogenous formaldehyde can produce different lesions, such as single-strand (SSB) and double-strand DNA breaks (DSB), DNA-protein crosslinks (DPCs), base lesions, and DNA inter- and intra-strand crosslinks. Specialized DNA repair pathways are activated following formaldehyde-induced DNA damage to safeguard genome stability. Formaldehyde-DNA-induced lesions are repaired by DNA damage response repair pathway (DDR), homologous recombination (HR), nucleotide excision repair (NER), base excision repair (BER) and translesion synthesis (TLS). DPCs are predominantly resolved by DPCs-proteolysis repair systems that involve SPRTN and Wss1/2, the Fanconi complex and the proteasome system.

Fig. 6.

Inflammatory signalling pathways activated by mtDNA. In mammalian cells, the release of mtDNA into the cytosol induces different inflammatory signalling pathways, including endosomal localized TLR9, cGAS-STING or the cytosolic inflammasome (AIM2 or NLRP3).