Secretory mitophagy is a novel pro-survival and pro-growth mechanism for Neurofibromatosis Type 2 cancers

Abstract

Neurofibromatosis Type 2 (NF2) is a hereditary cancer caused by a chromosomal mutation which induces loss-of-function of the tumor suppressor protein Merlin. The physical effects of the mutation-induced tumors include hearing loss, tinnitus and a loss in balance.
Currently, most therapies available are palliative and involve treatments to minimize pain and neurologic dysfunction, rather than destroying the cancer. There is a need to study new mechanisms of tumor growth. A hallmark of cancer is metabolic reprogramming. Under oxidative stress, mitochondria undergo changes (fission or fusion) to support the metabolic needs of the cancer. Autophagy, or self-eating, is a process to recycle damaged or unwanted proteins within a cell to the lysosome to survive. Mitophagy is the removal of damaged mitochondria regulated by mitochondrial fission molecules (FIS1 and PINK). Our team discovered an alternative pathway known as secretory mitophagy, which is the export of damaged mitochondria into extracellular vesicles. We observed Merlin, FIS1, and PINK1 within these vesicles. We hypothesize that secretory mitophagy is a cell survival and pro-growth mechanism used by
cancer cells to withstand oxidative stress and export tumor suppressor molecules. Chemically induced oxidative stress and lysosomal blockade of meningioma cancer cells lead to increased cell survival and greater levels of secretory mitophagy. Merlin co-located via
immunoprecipitation of PINK1+ EVs. A siRNA knock-down of FIS1 with oxidative stress reduced secretory mitophagy and cell survival. Overall, secretory mitophagy is an adaptive pathway used by cancer to endure greater levels of toxicity and export tumor suppressor
molecules for unchecked growth.