Panigrahi, Debasna Pritimanjari (2022) Deciphering the Role of MTP18 in Mitophagy and its Targeting for Apoptosis Induction in Oral Squamous Cell Carcinoma. PhD thesis.
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MTP18, a novel human nuclear-encoded protein with a molecular weight of 18 kDa, localized to the inner mitochondrial membrane, has a vital role in maintaining mitochondrial morphology and cell survival. In this study, we have investigated the role of MTP18 in mitophagy activation to clear dysfunctional mitochondria and its physiological significance in cell survival of oral squamous cell carcinoma (OSCC). Our study identified MTP18 as a mitophagy receptor to target damaged mitochondria into the autophagosomes for elimination and degradation. Interestingly, MTP18 interacts with LC3 through its LC3 interacting region (LIR) to induce mitochondrial autophagy, and mutation in the LIR motif inhibits this interaction leading to suppress mitophagy. Further, we established that Parkin-mediated proteasomal degradation of the outer mitochondrial membrane is essential for the interaction of LC3 and MTP18 to successful mitophagy. In this setting, we conclude MTP18 provides a survival advantage to the OSCC in exposure to cellular stress, and inhibition of MTP18-dependent mitophagy effectively reduces cell growth and induces cell death in OSCC. In addition, we have identified a novel inhibitor for MTP18 named S28, which promotes stress-induced mitochondrial hyperfusion (SIMH) in OSCC by limiting MTP18 mediated mitochondrial fission. Mechanistically, S28-mediated SIMH triggers loss of mitochondrial membrane potential, leading to the generation of mitochondrial superoxide followed by apoptosis. Intriguingly, it showed that S28-stimulated mitochondrial superoxide enhances lysosomal membrane permeabilization, resulting in decreased lysosomal pH, which entertained impairment of autophagosome-lysosome fusion. Furthermore, S28 in the combination of FDA-approved anticancer drugs inhibits cell viability and displays enhanced apoptosis suggesting the anticancer drugs exhibit better therapeutic response in MTP18 inhibition conditions in OSCC. In addition, our study unraveled that Abrus agglutinin (AGG), a plant lectin, promotes autophagy through inhibition in the expression of MTP18 in OSCC. We found that AGG-induced autophagy triggers loss of p62 and Nrf2 expression in OSCC. It showed that Nrf2 expression is restored in the presence of 3-methyladenine and Bafilomycin-A1, establishing the role of autophagy in the modulation of Nrf2 through p62. Moreover, we found that Nrf2 inhibition by AGG results in ROS accumulation followed by apoptosis and subsequently inhibits tumor growth in DMBA-induced oral carcinogenesis. Hence, targeting MTP18 may serve as a potential therapeutic for oral cancer treatment.
|Item Type:||Thesis (PhD)|
|Uncontrolled Keywords:||MTP18; Mitophagy; Mitochondrial fusion; Apoptosis; Oral squamous cell carcinoma|
|Subjects:||Life Science > Molecular Meidicine|
Life Science > Cancer Biology
|Divisions:||Sciences > Department of Life Science|
|Deposited By:||IR Staff BPCL|
|Deposited On:||18 Dec 2022 23:14|
|Last Modified:||18 Dec 2022 23:14|
|Supervisor(s):||Bhutia, Sujit Kumar|
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