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Updated: May 29, 2025

Analyses of Mitochondrial Calcium Influx in Isolated Mitochondria and Cultured Cells
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Berberine is a Novel Mitochondrial Calcium Uniporter Inhibitor that Disrupts MCU-EMRE Assembly

Haixin Zhao1,2, Siqi Chen1,3, Nian Cao1,4

  • 1Nanhu Laboratory, National Center of Biomedical Analysis, 27 Tai-Ping Road, Beijing, 100039, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|February 8, 2025
PubMed

Insights

Berberine inhibits the mitochondrial calcium uniporter (MCU) by blocking calcium entry into mitochondria. This safe, FDA-approved drug shows potential for treating diseases linked to mitochondrial calcium imbalance.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Pharmacology

Background:

  • The mitochondrial calcium uniporter (MCU) complex regulates mitochondrial Ca2+ uptake, vital for cellular energy and apoptosis.
  • MCU dysfunction is linked to neurodegenerative, cardiac, and cancerous diseases.
  • Developing specific MCU inhibitors for therapeutic use remains a significant challenge.

Purpose of the Study:

  • To identify a safe and effective inhibitor of the mitochondrial calcium uniporter (MCU) from an FDA-approved drug library.
  • To investigate the mechanism of action of Berberine as an MCU inhibitor.
  • To evaluate the therapeutic potential of Berberine in a preclinical model of myocardial injury.

Main Methods:

  • Virtual screening of an FDA-approved drug library to identify MCU inhibitors.
  • Mitochondrial localization studies and biochemical assays to determine Berberine's binding site on MCU.
  • Assessment of Berberine's effect on mitochondrial Ca2+ uptake and its protective role in an in vivo model of ischemia/reperfusion injury.

Main Results:

  • Berberine was identified as a potent MCU inhibitor.
  • Berberine localizes to mitochondria and directly binds to the MCU juxtamembrane loop, disrupting MCU-EMRE interaction and inhibiting Ca2+ influx.
  • Berberine pretreatment reduced mitochondrial Ca2+ overload and protected against ischemia/reperfusion-induced myocardial injury in mice.

Conclusions:

  • Berberine is a potent inhibitor of the mitochondrial calcium uniporter (MCU).
  • Berberine's mechanism involves direct binding to MCU, disrupting its interaction with EMRE.
  • Berberine presents a safe and promising therapeutic strategy for conditions involving aberrant mitochondrial calcium homeostasis.
Keywords:
EMREMCU (mitochondrial calcium uniporter)berberinemitochondrial calcium signalingmyocardial injurysmall molecules

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