FUNDC1 modulates mitochondrial defects and pancreatic β-cell dysfunction under lipotoxicity

Area of Science:

• Metabolic disorders
• Mitochondrial biology
• Cellular homeostasis

Background:

• Insulin resistance and metabolic disorders are linked to mitochondrial dysfunction.
• Mitophagy is crucial for maintaining mitochondrial quality control.
• FUNDC1 is a key mediator of mitophagy.

Purpose of the Study:

• To investigate the role of FUNDC1 in pancreatic beta-cell dysfunction under lipotoxicity.
• To determine if FUNDC1 can prevent or ameliorate diet-induced metabolic disorders.

Main Methods:

• Utilized pancreatic MIN6 cells and mouse models.
• Manipulated FUNDC1 expression (deficiency and overexpression).
• Induced lipotoxicity using palmitate and high-fat diet (HFD).
• Assessed mitochondrial function, endoplasmic reticulum stress, cell death, and insulin sensitivity.

Main Results:

• FUNDC1 deficiency worsened palmitate-induced mitochondrial dysfunction, cell death, and insulin insensitivity in MIN6 cells.
• FUNDC1 overexpression protected MIN6 cells against palmitate-induced damage.
• Pancreatic-specific FUNDC1 overexpression in mice alleviated HFD-induced insulin resistance and obesity.
• FUNDC1 overexpression ameliorated mitochondrial defects and ER stress in HFD-fed mice.

Conclusions:

• FUNDC1 is essential for protecting pancreatic beta cells from lipotoxicity-induced mitochondrial defects.
• FUNDC1 plays a critical role in preventing apoptosis and dysfunction of pancreatic beta cells.
• Targeting FUNDC1 may offer a therapeutic strategy for insulin resistance and metabolic disorders.