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