Saturday, May 18, 2024
5/18/2024
Tumor metabolic reprogramming is a hallmark of cancer progression, survival, and therapeutic resistance. A targetable class of cancer metabolic adaptation exploits mitophagy, a specialized autophagy pathway known to be linked to the cancer phenotype. Mitophagy selectively eliminates dysfunctional mitochondria by targeting them, via autophagosome shuttling, to the lysosome for degradation. Cancer cell mitophagy is triggered by elevated oxidative stress and mitochondria DNA damage caused by hypoxia, radiotherapy, molecular therapy, and immunotherapy. A high mitophagy demand can overwhelm the lysosome capacity resulting in the accumulation of damaged mitochondria that is harmful to the cell, and can suppress biogenesis of healthy mitochondria. We hypothesize that the newly discovered process of secretory mitophagy exports damaged mitochondrial fission-released segments to reduce the overload pressure on the lysosomal system, and thereby sustains cancer cell survival in the face of therapeutic mitochondrial stress. We have discovered a form of secretory mitophagy occurring in vivo in a growing solid tumor. Our molecular analysis of the full repertoire of extracellular vesicles (EV) shed into the resident tumor interstitial fluid (IF) in vivo yielded a rich set of information about the functional state of mitochondria within the tumor cells, and the host cells. Within tumor interstitial fluid, and within the culture media of cancer cells undergoing oxidative stress, we identified an EV-packaged full set of mitochondria molecules comprising the peripheral fission pinched-off segment of the mitochondrial organelle. It has recently been found that peripheral mitophagy fission, regulated by mitochondrial fission 1 protein (FIS1), is a key essential regulator of mitophagy, and is distinct from mid-zone mitochondria fission associated with mitochondria biogenesis. We also found that mitophagy inducer PTEN induced kinase 1 (PINK1) cleavage status (full length versus cleaved), is prominently reflected in the set of mitochondrial proteins exported within IF EVs, and may constitute a new quantitative measurement tool to monitor the real-time state of tumor intracellular mitophagy. Our findings raise important mechanistic questions, that we will explore in the Aims, concerning the unknown intracellular steps of secretory mitophagy and how the content of the exported EVs reflects the internal mitophagy state. Under Aim 1 we will test the hypothesis that peripheral fission secretory mitophagy is induced by high mitophagy demands that overwhelm lysosomal engulfment, and explore if secretory mitophagy is distinct from secretory autophagy within the murine 4T1 and human MDA-MB-231 triple negative breast cancer cell lines. Under Aim 2 we will test the hypothesis that the ratio of full length to cleaved PINK1 is elevated (mitochondria damage sensor) within the exported murine syngeneic breast tumor interstitial fluid EVs, following treatment with mitophagy inducers Mito-CP and Rapamycin. The outcome is new understanding of the importance of secretory mitophagy that can constitute an important therapeutic target, and a new clinically relevant means of monitoring the in vivo state of mitophagic flux within the tumor microenvironment.
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