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Mitochondrial Structure-Function Relationship in KRAS-induced Senescence During Neoplastic Transform

Graduate Student Seminar Series | Mayank Saini | February 12, 2024

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Abstract:

Mitochondria, traditionally known for their energy role, now play a vital part in various cellular functions and redox balance. Cellular senescence, characterized by stable cell cycle arrest, has emerged as a multifaceted process with implications in both tumour suppression and progression. Oncogene activation is widely recognized for promoting cell proliferation, an event crucial for tumorigenesis across various cancer types. Moreover, it concurrently poses genetic stress that can lead to irreversible growth arrest leading to oncogene-induced senescence (OIS). Mitochondrial structure-function changes are linked to specific oncogenes like KRAS, influencing tumorigenic or senescent outcomes. We propose that mitochondria are part of the pivotal switch that governs the decision between a cell to undergo neoplastic transformation or to maintain senescence during oncogene activation. Preliminary data reveals mitochondrial length heterogeneity in neoplastic transformed cells expressing higher p16 (senescent marker), regulated by Drp-1 (mitochondrial fission protein).  We then aimed to understand how this structure heterogeneity is linked to mitochondrial function changes (oxidation). This led to the development of Mito-Sim2, a novel approach to visualize oxidative status influencing the structure of individual mitochondria. Initial analysis revealed a certain oxidation level is maintained by smaller fused mitochondrial networks with distinct homeostatic zones. Since OIS utilizes free radicals for senescence induction by exploiting mitochondrial metabolic reprogramming, we plan to use Mito-Sim2 to understand how mitochondrial oxidation status impacts its structure during oncogene activation. Transfecting non-transformed cells with KRAS mutants yields variable senescence expression, while OIS effects in neoplastic cells need to be explored. Future plans include clinical studies for comprehensive insights. This project will hopefully help us understand the intricate relationship of mitochondria in oncogene-triggered cellular senescence (OIS) and neoplastic transformation, promising insights for cancer intervention.

About the Speaker:
Mayank's broad interest lies in disease-oriented research, particularly in cancer and ageing. After clearing various national eligibility tests he joined the Mitochondrial Structure Function Lab, where he is trying to unravel the mystery of the underlying mitochondrial biology in the process of senescence and cancer. He obtained his bachelor’s degree from Sri Venkateswara College, Delhi University in Biochemistry and a master's in Biotechnology from the University of Hyderabad. His master's dissertation work was focused on Expression and Characterization studies of proteins which was supported by a scholarship from DBT, Govt. of India. Apart from science, he loves outdoor sports, road trips, travelling, spending time with friends and occasional cooking (Of course, he is a big-time foodie!).

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