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<p>Many metabolic diseases show mitochondrial abnormalities because of dysfunction of complex I (CI). Therefore, the discovery of drugs that target the CI is of great interest. Berberine (BBR) is a botanic agent and has been included in the latest ESC/EAS Guidelines for the management of dyslipidemias. Here, we showed that BBR enters hepatocyte mitochondria after oral administration and improves glucose and lipid metabolism by reducing oxidative phosphorylation in hepatocytes. BBR inhibits CI function rapidly, selectively, and reversibly, not by directly inhibiting CI enzyme activity but by reducing the abundance of CI in the mitochondria through dissociation of CI. BBR directly binds to and activates Sirtuin 3 (SIRT3), thereby reducing acetylation of the catalytic subunit NDUFS1 in the N-module of CI, leading to dissociation of mitochondrial CI. Conclusively, BBR, as a mitochondria-homing agent, selectively and reversibly dissociates mitochondrial CI through SIRT3-dependent NDUFS1 deacetylation to improve hepatocellular glucose and lipid metabolism, highlighting that CI may be a promising target for innovative natural products to treat metabolic diseases.</p>

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Berberine dissociates mitochondrial complex I by SIRT3-dependent deacetylation of NDUFS1 to improve hepatocellular glucose and lipid metabolism

  • 期刊论文

  • 发表日期：

    2025年6月6日

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  • Xuekai Wang,
  • Hu Li,
  • Jianrui Li,
  • Lei Lei,
  • Jingchen Xu,
  • Han Sun,
  • Jiayu Li,
  • Jing Jiang,
  • Hongying Li,
  • Mei Tang,
  • Biao Dong,
  • Yue Gong,
  • Jiandong Jiang,
  • Zonggen Peng

摘要

Many metabolic diseases show mitochondrial abnormalities because of dysfunction of complex I (CI). Therefore, the discovery of drugs that target the CI is of great interest. Berberine (BBR) is a botanic agent and has been included in the latest ESC/EAS Guidelines for the management of dyslipidemias. Here, we showed that BBR enters hepatocyte mitochondria after oral administration and improves glucose and lipid metabolism by reducing oxidative phosphorylation in hepatocytes. BBR inhibits CI function rapidly, selectively, and reversibly, not by directly inhibiting CI enzyme activity but by reducing the abundance of CI in the mitochondria through dissociation of CI. BBR directly binds to and activates Sirtuin 3 (SIRT3), thereby reducing acetylation of the catalytic subunit NDUFS1 in the N-module of CI, leading to dissociation of mitochondrial CI. Conclusively, BBR, as a mitochondria-homing agent, selectively and reversibly dissociates mitochondrial CI through SIRT3-dependent NDUFS1 deacetylation to improve hepatocellular glucose and lipid metabolism, highlighting that CI may be a promising target for innovative natural products to treat metabolic diseases.