UC Berkeley

Cell biology has numerous occurrences when the ‘Goldilocks principle’ is relevant, when the ‘just right’ amount is essential for human health. For reactive molecules and metal nutrients, this balance is the distinction between optimal signaling functions, toxicity, and deficiency. Demonstrating this balance, this work focuses on investigating two examples of perturbed cellular levels: formaldehyde excess in relation to one-carbon metabolism and copper deficiency in relation to non-alcoholic fatty liver disease (NAFLD). Formaldehyde is a carcinogen from exogenous exposures but also endogenous pathways, such as N-demethylation reactions. We investigated formaldehyde chemical biology in contexts of protein reactivity and metabolism to characterize its targets and physiological roles. Here, we identified formaldehyde as another key one-carbon unit that also participates as a signaling molecule—particularly in one-carbon metabolism, which maintains folate and S-adenosylmethionine (SAM) as the primary one-carbon units for methylation and metabolic processes. We employed multi-omics approaches to identify and characterize lipid, metabolite, and protein targets of formaldehyde. Studying the downstream effects of formaldehyde on cellular methylation status, we uncovered mechanisms of formaldehyde in disrupting metabolic balance of one-carbon metabolism and other potential pathways. Copper is a redox-reactive transition metal that causes oxidative stress and damage if left unregulated. Therefore, copper homeostasis is precisely regulated through copper import, export, trafficking, and redox proteins. While copper deficiency and lipogenesis have been linked, the connection is still unclear. We performed multi-omics analyses in high-fat diet-induced NAFLD mouse models and liver-targeted copper supplementation to identify targets and therapeutic pathways of copper-dependent lipid metabolism and regulation. Taken together, we have begun to decipher intriguing interactions in liver health and disease.