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
Affiliations
Ying Jiang
Departments of Pharmacology, University of Illinois at Chicago, Chicago, IL, 60612, USA; Center for Informational Biology, University of Electronic Science and Technology of China, 610054, China
Sarah Krantz
Departments of Pharmacology, University of Illinois at Chicago, Chicago, IL, 60612, USA
Xiang Qin
Center for Informational Biology, University of Electronic Science and Technology of China, 610054, China
Shun Li
Center for Informational Biology, University of Electronic Science and Technology of China, 610054, China
Hirushi Gunasekara
Chemistry, University of Illinois at Chicago, Chicago, IL, 60612, USA
Young-Mee Kim
Departments of Pharmacology, University of Illinois at Chicago, Chicago, IL, 60612, USA; University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL, 60612, USA
Adriana Zimnicka
Departments of Pharmacology, University of Illinois at Chicago, Chicago, IL, 60612, USA
Misuk Bae
Anesthesiology, University of Illinois at Chicago, Chicago, IL, 60612, USA
Ke Ma
Research Resources Center, University of Illinois at Chicago, Chicago, IL, 60612, USA
Peter T. Toth
Departments of Pharmacology, University of Illinois at Chicago, Chicago, IL, 60612, USA; Research Resources Center, University of Illinois at Chicago, Chicago, IL, 60612, USA
Ying Hu
Chemistry, University of Illinois at Chicago, Chicago, IL, 60612, USA
Ayesha N. Shajahan-Haq
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, 20057, USA
Hemal H. Patel
VA San Diego Health System and Department of Anesthesiology, University of California at San Diego, San Diego, CA, 92161, USA
Saverio Gentile
Medicine, University of Illinois at Chicago, Chicago, IL, 60612, USA; University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL, 60612, USA
Marcelo G. Bonini
Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, 60614, USA
Jalees Rehman
Departments of Pharmacology, University of Illinois at Chicago, Chicago, IL, 60612, USA; Medicine, University of Illinois at Chicago, Chicago, IL, 60612, USA; University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL, 60612, USA
Yiyao Liu
Center for Informational Biology, University of Electronic Science and Technology of China, 610054, China
Richard D. Minshall
Departments of Pharmacology, University of Illinois at Chicago, Chicago, IL, 60612, USA; Anesthesiology, University of Illinois at Chicago, Chicago, IL, 60612, USA; University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL, 60612, USA; Corresponding author. Departments of Anesthesiology and Pharmacology, University of Illinois at Chicago, Chicago, IL, 60612, USA.
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.
