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FUNDC1 interacts with FBXL2 to govern mitochondrial integrity and cardiac function through an IP3R3-dependent manner

Jun Ren1,2, Mingming Sun1,3, Hao Zhou3,4

  • 1Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China.

Science Advances
|September 17, 2020
PubMed

Insights

Defective mitophagy impairs heart function in obesity. Researchers found that the mitophagy protein FUNDC1 interacts with FBXL2 to regulate mitochondrial calcium, protecting against diet-induced heart damage.

Area of Science:

  • Mitochondrial biology
  • Cardiovascular research
  • Cellular signaling

Background:

  • Defective mitophagy is linked to obesity complications.
  • Mitochondrial calcium (Ca2+) homeostasis is crucial for cardiac function.
  • IP3R3 is a key regulator of intracellular Ca2+ release.

Purpose of the Study:

  • To investigate the role of mitophagy protein FUNDC1 in obesity-related cardiac dysfunction.
  • To identify the molecular mechanisms underlying mitochondrial Ca2+ dysregulation in obesity.
  • To explore the interaction between FUNDC1 and the ubiquitin ligase complex FBXL2.

Main Methods:

  • Utilized FUNDC1 knockout (FUNDC1-/-) mice fed a high-fat diet.
  • Performed mass spectrometry and co-immunoprecipitation to identify protein interactions.
  • Analyzed cardiac remodeling, mitochondrial function, cell death, and Ca2+ levels.
  • Investigated the impact of FBXL2 activation/inhibition and IP3R3 modulation.

Main Results:

  • FUNDC1 deficiency exacerbated high-fat diet-induced cardiac remodeling, mitochondrial dysfunction, and Ca2+ overload.
  • An interaction between FUNDC1 and FBXL2 was identified, crucial for IP3R3 degradation.
  • FBXL2 activation or IP3R3 inhibition protected against lipotoxicity-induced cardiac damage.
  • FUNDC1 deficiency altered the degradation rates of FBXL2 and IP3R3.

Conclusions:

  • The interaction between FUNDC1 and FBXL2 acts as a gatekeeper for mitochondrial Ca2+ homeostasis.
  • This interaction is essential for preserving cardiac function in the context of obesity and lipotoxicity.
  • Targeting the FUNDC1-FBXL2-IP3R3 axis may offer therapeutic strategies for obesity-related heart disease.

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