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Author Spotlight: Transmitochondrial Cybrid Generation Using Cancer Cell Lines
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Mitochondrial metabolic reprogramming by SIRT3 regulation ameliorates drug resistance in renal cell carcinoma

Young-Ran Gu1, Jinu Kim1,2, Joon Chae Na1

  • 1Department of Urology, Urological Science Institute, Yonsei University College of Medicine, Seoul, Korea.

Plos One
|June 7, 2022
PubMed

Insights

Sirtuin3 (SIRT3) enhances mitochondrial function in clear cell renal cell carcinoma (ccRCC) by reprogramming metabolism. Overexpressing SIRT3 boosts sensitivity to anticancer drugs, showing synergistic effects with resveratrol.

Area of Science:

  • Oncology
  • Mitochondrial Biology
  • Cancer Metabolism

Background:

  • Clear cell renal cell carcinoma (ccRCC) is characterized by metabolic dysregulation, including increased glycolysis and lipid accumulation, leading to mitochondrial dysfunction.
  • Sirtuin3 (SIRT3), a mitochondrial deacetylase, is crucial for maintaining mitochondrial integrity and function, and its downregulation is implicated in ccRCC development and progression.

Purpose of the Study:

  • To investigate the role of SIRT3 in regulating mitochondrial biogenesis and function within ccRCC.
  • To explore the therapeutic potential of modulating SIRT3 levels in ccRCC treatment.

Main Methods:

  • SIRT3 overexpression in ccRCC cells.
  • Assessment of mitochondrial function, including glucose uptake and membrane potential.
  • Evaluation of cell viability in response to anticancer drugs (Resveratrol, Everolimus, Temsirolimus) in ccRCC with varying SIRT3 levels.

Main Results:

  • SIRT3 overexpression alone decreased glucose uptake and increased mitochondrial membrane potential in ccRCC cells.
  • ccRCC cells with overexpressed SIRT3 exhibited enhanced sensitivity to anticancer drugs, including resveratrol and mTOR inhibitors.
  • Combination therapy of SIRT3 overexpression with resveratrol demonstrated a synergistic lethal effect on ccRCC cells.

Conclusions:

  • SIRT3 plays a critical role in improving mitochondrial function in ccRCC through metabolic reprogramming.
  • Modulating SIRT3 activity can enhance the efficacy of conventional anticancer therapies.
  • Targeting SIRT3, particularly in combination with resveratrol, presents a promising synergistic therapeutic strategy for ccRCC.

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