Secretory Mitophagy: A new target for ovarian cancer drug resistance

Authors

  • Atharva Tyagi Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA
  • Arnav Bandam Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA
  • Rithvik Gabbireddy Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA
  • Angela Rojas Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA
  • Purva Gade Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA
  • Marissa Howard Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA
  • Lance Liotta Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA

Abstract

Ovarian cancer, which forms in the fallopian tubes, is characterized by asymptomatic early stages, resulting in late detection, a poor prognosis, and a high fatality rate. Additionally, ovarian cancer has higher rates of drug resistance. Recent research has highlighted the importance of mitochondrial dynamics, particularly fusion and fission, in ovarian cancer development and drug resistance. Mitochondrial fusion combines two mitochondria to reduce stress and share mitochondrial DNA, whereas fission separates mitochondria and allows for the elimination of damaged components via mitophagy. We discovered a unique mechanism called secretory mitophagy, in which damaged mitochondrial proteins and components are ejected via extracellular vesicles and mitochondrial fission. Our research identified the FIS1 protein as a critical fission initiator. Cancer cells enhance mitophagy in response to oxidative stress. Unexpectedly, ovarian cancer cells have enlarged mitochondria, suggesting enhanced fusion. We propose that increased mitochondrial fusion leads to chemoresistance in ovarian cancer. By inhibiting FIS1, we expect enhanced mitochondrial fusion, connecting fusion to drug resistance. We further hypothesize that secretory mitophagy allows ovarian cancer cells to withstand significant oxidative stress. To test these assumptions, we used siRNA against FIS1, treated cells with mitophagy inducers (Carbonyl cyanide m-chlorophenyl hydrazone (CCCP)) and lysosomal inhibitors (Bafilomycin A), and then measured cell viability and toxicity. Our tests included western blots for PINK1, FIS1, CD81, TOM20, and DRP1. Our data suggests mitochondrial fusion and secretory mitophagy play critical roles in ovarian cancer drug resistance and survival pathways, respectively. Targeting these mechanisms may provide new treatment options for this aggressive disease.

Published

2024-10-13

Issue

Section

College of Science: School of Systems Biology