Gut microbiota-derived lysine phenylacetylation impairs mitochondrial function and is alleviated by SIRT3

Area of Science:

• Microbiology
• Metabolic Disorders
• Molecular Biology

Background:

• Gut microbiota (GM) disturbances are implicated in metabolic disorders.
• Short-chain fatty acids from GM are key signaling molecules.
• Lysine modifications play crucial roles in cellular processes.

Purpose of the Study:

• To identify and characterize novel microbiota-derived post-translational modifications.
• To investigate the role of phenylacetylation (Kpaa) in metabolic dysfunction.
• To explore the link between Kpaa, mitochondrial function, and metabolic diseases.

Main Methods:

• Induction of obesity in mice using a high-fat diet.
• Proteomic analysis to identify lysine modifications.
• Measurement of hepatic Kpaa levels and SIRT3 activity.
• Investigation of PAA effects on mitochondrial function and insulin signaling in vitro and in vivo.

Main Results:

• A novel lysine modification, phenylacetylation (Kpaa), derived from GM's phenylacetic acid (PAA) pathway was identified.
• Hepatic Kpaa levels were elevated in diet-induced obesity and reduced by SIRT3.
• PAA disrupted mitochondrial function and impaired insulin signaling.
• PAA-induced Kpaa of HSP60 triggered the mitochondrial unfolded protein response, reversible by SIRT3.
• Low hepatic SIRT3 correlated with high Kpaa in human obesity and MASH.

Conclusions:

• Microbiota-derived phenylacetylation (Kpaa) is a novel modification linked to metabolic dysfunction.
• Kpaa contributes to mitochondrial dysfunction and impaired insulin signaling.
• SIRT3 plays a protective role against PAA-induced metabolic derangements.
• Kpaa represents a potential therapeutic target for metabolic dysfunction-associated steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis (MASH).