Redox Biology (Jun 2022)

Caveolin-1 controls mitochondrial damage and ROS production by regulating fission - fusion dynamics and mitophagy

  • Ying Jiang,
  • Sarah Krantz,
  • Xiang Qin,
  • Shun Li,
  • Hirushi Gunasekara,
  • Young-Mee Kim,
  • Adriana Zimnicka,
  • Misuk Bae,
  • Ke Ma,
  • Peter T. Toth,
  • Ying Hu,
  • Ayesha N. Shajahan-Haq,
  • Hemal H. Patel,
  • Saverio Gentile,
  • Marcelo G. Bonini,
  • Jalees Rehman,
  • Yiyao Liu,
  • Richard D. Minshall

Journal volume & issue
Vol. 52
p. 102304

Abstract

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As essential regulators of mitochondrial quality control, mitochondrial dynamics and mitophagy play key roles in maintenance of metabolic health and cellular homeostasis. Here we show that knockdown of the membrane-inserted scaffolding and structural protein caveolin-1 (Cav-1) and expression of tyrosine 14 phospho-defective Cav-1 mutant (Y14F), as opposed to phospho-mimicking Y14D, altered mitochondrial morphology, and increased mitochondrial matrix mixing, mitochondrial fusion and fission dynamics as well as mitophagy in MDA-MB-231 triple negative breast cancer cells. Further, we found that interaction of Cav-1 with mitochondrial fusion/fission machinery Mitofusin 2 (Mfn2) and Dynamin related protein 1 (Drp1) was enhanced by Y14D mutant indicating Cav-1 Y14 phosphorylation prevented Mfn2 and Drp1 translocation to mitochondria. Moreover, limiting mitochondrial recruitment of Mfn2 diminished formation of the PINK1/Mfn2/Parkin complex required for initiation of mitophagy resulting in accumulation of damaged mitochondria and ROS (mtROS). Thus, these studies indicate that phospho-Cav-1 may be an important switch mechanism in cancer cell survival which could lead to novel strategies for complementing cancer therapies.

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