Research Projects

Tumor hypoxia is defined as a condition where cancer cells live under limited oxygen and nutrient availability because of the chaotic and disordered vascularisation to a rapidly growing cancer. While hypoxia is lethal for many cells, a subpopulation of tumor cells become able to adapt to hypoxic conditions, and often exhibit radio and chemo resistance1,2. Numerous strategies have been developed to overcome hypoxia induced resistance, nevertheless, their clinical use is compromised because of limited efficacy and side effects3. An alternative approach would be to identify and target the adaptive mechanisms that help cancer cells to survive under hypoxia induced stress conditions. Various studies have confirmed that hypoxia leads to alteration in mitochondrial homeostasis, including decreased oxidative phosphorylation and cytochrome c oxidase activity, increased ROS production by electron transport chain due to inefficient electron transfer. This paradoxical effect of increased ROS under low oxygen tension can damage various cellular macromolecules as well as mitochondria themselves, thereby leading to mitochondrial dysfunction4. To mitigate these damage, hypoxic cells often upregulate mitochondria specific autophagy or mitophagy (a fundamental process of clearing damaged mitochondria) to maintain the homeostasis between the cellular energy demand and redox homeostasis and that eventually contributes to therapeutic resistance5,6. Mitophagy machinery also allows hypoxic cells to reduce mitochondrial mass, thereby limiting ROS production and maximizing the efficient use of available oxygen7. Therefore, the dependency of hypoxic cells on cellular mitophagy is enormous and thus could be an attractive treatment option to tackle the highly resistant hypoxic tumor populations. However, the signaling cascades that link the sensing of hypoxia to the activation of mitophagy are not well understood. Recently, we have shown that members of the tripartite motif family (TRIM) of proteins, namely TRIM5 and TRIM27 can maintain mitochondrial homeostasis by acting as mitophagy receptor-regulator and through elimination of damaged mitochondria8,9,10. In addition, several other TRIMs are reported to be involved in hypoxia induced cancer progression into malignant phenotype11. Nevertheless, their role in tumor hypoxia induced mitophagy remain unidentified. The TRIM family of proteins is among the biggest recognized single protein RING finger E3 ubiquitin ligases and our observation that the ligase activity of TRIM5 is crucial for its mitophagy regulation further raises the possibility of considering TRIM proteins as a druggable candidate to tackle mitophagy induced drug resistance12. In this proposed project, our goal is to identify the in-depth mechanism of how tumor cells of hypoxic regions upregulate mitophagy and whether TRIM protein/s can be targeted as a novel modulator of mitophagy to develop advanced therapeutics.