Novel Role for Phosphorylated Merlin and Mitophagy Triggered PINK-1 in Neurofibromatosis Type 2 Meniningiomas

Authors

  • EMMA MATHEW Center of Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA
  • Angela Rojas Center of Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA
  • ANJU ADVANI Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA
  • LAYLA HASANZADAH Center of Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA
  • LINDA HUANG 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
  • Ali Andalibi School of Systems Biology, George Mason University, Fairfax, VA
  • Lance Liotta Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA

DOI:

https://doi.org/10.13021/jssr2023.3917

Abstract

Neurofibromatosis Type 2 (NF2) is an inherited cancer caused by a mutation of the Merlin gene on chromosome 22. Merlin is an important tumor suppressor that regulates key signaling pathways important for cell growth and migration. Mitophagy is required by cancer cells for survival under stress. Unfragmented PINK-1 triggers fission and mitophagy, and damaged mitochondria fragments are exported by extracellular vesicles (EVs). We hypothesize that Merlin is associated with PINK-1 when under oxidative stress and is removed to EVs during mitophagy. This predicts that oxidative stress will shut down the tumor suppressor function of Merlin. By quantifying the relative levels of phosphorylated and total forms of PINK-1 and Merlin in EVs exported by cultured meningioma cells (subjected to stress) and also evaluating Merlin and PINK-1 in patient meningiomas and schwannomas, we discovered a close association between PINK-1 and Merlin in both patients and in the EVs derived from cultured meningiomas in vitro, confirming our hypothesis. Further understanding of the functional relationship of PINK-1 and Merlin phosphorylation during mitophagy will provide a new set of therapeutic targets for NF2 and other diseases causally associated with defects in PINK1 regulation of mitophagy.

Published

2023-10-27

Issue

Section

College of Science: School of Systems Biology

Categories