Hepatic neddylation targets and stabilizes electron transfer flavoproteins to facilitate fatty acid β-oxidation

Area of Science:

• Biochemistry
• Cell Biology
• Metabolic Disorders

Background:

• Neddylation, a ubiquitination-like modification, regulates cell survival and proliferation.
• The role of neddylation in mammalian metabolism and its mitochondrial targets were previously unknown.
• Defects in electron transfer flavoproteins (ETFs) cause glutaric aciduria type II (GA-II), a fatty acid oxidation disorder.

Purpose of the Study:

• To investigate the physiological role of neddylation in mammalian metabolism.
• To identify mitochondrial targets of neddylation.
• To explore the link between neddylation, ETFs, and GA-II.

Main Methods:

• Generation of mouse models with liver-specific deficiency of NEDD8 or UBA3.
• Analysis of liver phenotype, including fatty liver, cellular senescence, and metabolic abnormalities.
• Assessment of ETF protein levels and neddylation status in response to neddylation inhibition and in GA-II patient mutations.

Main Results:

• Liver-specific deficiency of NEDD8 or UBA3 caused neonatal death, fatty liver, and hepatic cellular senescence.
• Neddylation inhibition decreased ETF levels and exacerbated fasting-induced steatosis.
• Electron transfer flavoproteins (ETFs) were identified as direct neddylation substrates, stabilized by neddylation against ubiquitination and degradation.
• GA-II patient mutations in ETFs impaired their neddylation.

Conclusions:

• Neddylation plays a critical role in hepatic metabolism by stabilizing ETFs.
• This study identifies ETFs as novel neddylation substrates and reveals a mechanism linking neddylation to fatty acid oxidation disorders like GA-II.
• Neddylation is essential for preventing neonatal fatty liver and maintaining metabolic homeostasis.