2. Academic Validation
  3. Elevated PINK1/Parkin-Dependent Mitophagy and Boosted Mitochondrial Function Mediate Protection of HepG2 Cells from Excess Palmitic Acid by Hesperetin

Elevated PINK1/Parkin-Dependent Mitophagy and Boosted Mitochondrial Function Mediate Protection of HepG2 Cells from Excess Palmitic Acid by Hesperetin

  • J Agric Food Chem. 2024 Jun 12;72(23):13039-13053. doi: 10.1021/acs.jafc.3c09132.
Wan Li 1 2,  Zhengnan Cai 1 2,  Florian Schindler 1 3,  Leila Afjehi-Sadat 4 5,  Bianca Montsch 6 7,  Petra Heffeter 6,  Elke H Heiss 8,  Wolfram Weckwerth 1 9
Affiliations

Affiliations

  • 1 Molecular Systems Biology (MOSYS), Department of Functional and Evolutionary Ecology, University of Vienna, Vienna 1030, Austria.
  • 2 Vienna Doctoral School of Ecology and Evolution, University of Vienna, Vienna 1030, Austria.
  • 3 Vienna Doctoral School of Pharmaceutical, Nutritional and Sports Sciences, University of Vienna, Vienna 1090, Austria.
  • 4 Mass Spectrometry (Core) Facility, University of Vienna, Vienna 1030, Austria.
  • 5 Research Support Facilities UBB, University of Vienna, Vienna 1030, Austria.
  • 6 Center for Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Vienna 1090, Austria.
  • 7 Department of Food Chemistry and Toxicology, University of Vienna, Vienna 1090, Austria.
  • 8 Department of Pharmaceutical Sciences, University of Vienna, Vienna 1090, Austria.
  • 9 Vienna Metabolomics Center (VIME), University of Vienna, Vienna 1030, Austria.
PMID: 38809522 DOI: 10.1021/acs.jafc.3c09132
Abstract

Deregulation of mitochondrial functions in hepatocytes contributes to many liver diseases, such as nonalcoholic fatty liver disease (NAFLD). Lately, it was referred to as MAFLD (metabolism-associated fatty liver disease). Hesperetin (Hst), a bioactive flavonoid constituent of citrus fruit, has been proven to attenuate NAFLD. However, a potential connection between its preventive activities and the modulation of mitochondrial functions remains unclear. Here, our results showed that Hst alleviates palmitic acid (PA)-triggered NLRP3 inflammasome activation and cell death by inhibition of mitochondrial impairment in HepG2 cells. Hst reinstates fatty acid oxidation (FAO) rates measured by seahorse extracellular flux analyzer and intracellular acetyl-CoA levels as well as intracellular tricarboxylic acid cycle metabolites levels including NADH and FADH2 reduced by PA exposure. In addition, Hst protects HepG2 cells against PA-induced abnormal energetic profile, ATP generation reduction, overproduction of mitochondrial Reactive Oxygen Species, and collapsed mitochondrial membrane potential. Furthermore, Hst improves the protein expression involved in PINK1/Parkin-mediated Mitophagy. Our results demonstrate that it restores PA-impaired mitochondrial function and sustains cellular homeostasis due to the elevation of PINK1/Parkin-mediated Mitophagy and the subsequent disposal of dysfunctional mitochondria. These results provide therapeutic potential for Hst utilization as an effective intervention against fatty liver disease.

Keywords

PINK1/Parkin-mediated mitophagy degradation; TCA cycle and fatty acid oxidation; hesperetin; metabolomics; mitochondrial dysfunction.

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