Targeting Mitochondria Metabolisms for Novel AML Therapy Development
Kirienko, Natasha V.; Carson, Daniel
Doctor of Philosophy
Mitochondrial dysfunction contributes to a wide variety of pathologies, including neurodegenerative diseases, cancer, metabolic diseases, and aging. As a consequence, oncogenesis and tumor progression heavily depends on the mitochondrial metabolism. I investigated the potential of using mitochondrial targeting drugs to selectively remove leukemia, a type of cancer that has been previously identified to be sensitive to mitochondria-targeting drugs. I optimized Hoeschst/PI dual-staining assay for quick, high-throughput screening of leukemia cell’ viability under mitochondria-targeting drugs treatments. Through combination of mitochondria-targeting drugs and anti-cancer chemotherapeutic agents, I observed high synergistic effect in the removal of leukemia in these combinations. I characterized several changes in mitochondria bioenergetic parameters that are correlated with the sensitivity of mitochondria-targeting drug to leukemia. These observations also applied to primary AML samples extracted from patients. Mitochondria health is actively surveilled by several different systems to ensure the preservation of cellular viability. Mitophagy is a conservative process that removes superfluous or damaged mitochondria. I identified 8 compounds with mitophagy activation effect that can stabilize PINK-1/PINK1 in C. elegans with my colleague Dr. Elissa Tjahjono. I observed these compounds induced selective removal of leukemia alone or in combination with other anti-cancer chemotherapeutic agents. Furthermore, these compounds reduced paralysis level in C. elegans model of neurodegenerative diseases. Taken together, activation of mitophagy using these compounds may be a novel method to develop selective therapy for leukemia and neurodegenerative diseases.