RBM15 impairs Hepatic Mitochondria and β-Oxidation through m

Abstract

Diabesity, defined as obesity accompanied by Type 2 diabetes mellitus, is characterized by metabolic dysfunction and mitochondrial impairment. Here, we investigate the role of N6-methyladenosine (m6A)-mediated RNA regulation in regulating hepatic mitochondrial function and fatty acid β-oxidation during diabesity progression. Diabesity was modeled in male C57BLKS/J db/db mice, with db/m lean mice as controls; in vitro models were established using primary hepatocytes isolated from male C57BL/6J mice exposed to high glucose and palmitate. Our results showed that MCM3 was significantly downregulated in diabesity models. MCM3 overexpression improved hepatic mitochondrial function and fatty acid β-oxidation. Mechanistically, MCM3 increased NRF2 in hepatocytes by competitive combination with KEAP1. In addition, RBM15 overexpression accelerated m6A-YTHDF2-mediated MCM3 mRNA decay. As expected, MCM3 knockdown negated the metabolic benefits of RBM15 knockdown. In conclusion, m6A-dependent MCM3 downregulation by RBM15/YTHDF2 impaired hepatic mitochondrial function and fatty acid β-oxidation in diabesity by reducing NRF2.

Key Findings

• MCM3 is significantly downregulated in diabesity models.
• MCM3 overexpression improves hepatic mitochondrial function and fatty acid β-oxidation.
• MCM3 increases NRF2 levels in hepatocytes by competitively binding KEAP1.
• RBM15 overexpression promotes m6A-YTHDF2-mediated MCM3 mRNA decay, reducing MCM3 and impairing mitochondrial function.
• Knockdown of MCM3 negates the metabolic benefits of RBM15 knockdown.

Clinical Significance

Citation

Chen Kai, Xiang Yi, Deng Daqinget al.. RBM15 impairs Hepatic Mitochondria and β-Oxidation through m Communications biology. 2026-Jul-18.