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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article number102304
JournalRedox Biology
Volume52
DOIs
StatePublished - Jun 2022

Keywords

  • Cav-1
  • Dynamin-related protein 1
  • Mitochondrial dynamics
  • Mitofusin 2
  • Mitophagy
  • mtROS

ASJC Scopus subject areas

  • Organic Chemistry
  • Clinical Biochemistry

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