Project 466794

The mitochondria is responsible for food metabolism and energy production inside the human body. In response to diverse mitochondrial stressors, eukaryotic cells initiate two distinct pathways, mitophagy and the integrated stress response (ISR), to reestablish mitochondrial homeostasis. However, little is known about the ISR signal relay mechanism and lots of debates exist around what is the main mitophagy pathway. In the context of intestine, the persistence of mitochondrial dysfunction can affect stem cell proliferation and trigger tumorigenesis, which emphasizes on the reliance of mitophagy and the ISR. We propose to study both the mitophagy and ISR pathways in intestinal stem cells (ISC). Our overarching goal is to define how mitophagy/ISR affect ISC differentiation and proliferation. The long term impact of our work will aid in better understanding of diseases such as inflammatory bowel disease and colorectal cancer.Aim1 is to establish the importance of a mitophagy pathway identified in our lab and the ISR pathway in mitochondrial homeostatsis in human colon cancer cell lines. We will induce stress on the mitochondria and knockdown specific proteins using shRNA to observe induction/deduction in ISR and mitophagy activities. Results will shed light into how mitophagy and ISR maintain mitochondrial homeostasis in intestinal cell line. Aim2 will utilize ex vivo knockoutintestinal organoids to examine how malfunctioning mitophagy and ISR impact ISC differentiation. Any impact on ISC differentiation will suggest mitophagy/ISR regulates stem cell fate. Our research is important due to very limited research available in the field and that our findings will aid in the development of promising therapeutics to target mitochondrial disease and cancer.