Theses and Dissertations

Date of Award

5-2023

Document Type

Dissertation

Degree Name

Ph.D.

Department

Basic Medical Sciences

Committee Chair

Santanu Dasgupta, Ph.D. and Ajay P. Singh, Ph.D

Advisor(s)

Dr. Ron Balczon, Dr. Seema Singh, Dr. Michele Schuler, Dr. Lyudmila Rachek

Abstract

Pancreatic cancer (PC) is a highly deadly malignancy with no effective biomarkers for early diagnosis, accurate monitoring and/or surveillance. Due to the late staged diagnosis in the majority of the cases, therapeutic interventions are limited resulting in high mortality. Recent studies continue to discover the diverse roles of mitochondria in pancreatic tumorigenesis, potentiating mitochondria as attractive targets for therapeutics and biomarker development. Although mitochondria have their own genome, most mitochondrial proteins (∼99%) are nuclear-encoded and imported into mitochondria by a specialized protein import system consisting of seven machineries. Among these machineries, translocase of the outer mitochondrial membrane (TOMM) machinery, comprising of various subunits serves as the gatekeeper of mitochondrial protein import for majority of the nuclear-transcribed proteins, thereby making it a crucial machinery for optimal mitochondrial functioning. Despite the knowledge about various roles mitochondria play in pancreatic ductal adenocarcinoma (PDAC) pathogenesis, the exact TOMM subunit(s) critical for PDAC progression has not been discovered yet. Furthermore, there are no studies about the role of the TOMM machinery in PDAC pathogenesis. Our study identified TOMM22 as the only TOMM subunit, which had both increased mRNA expression in PDAC and significant inverse association with patient survival by in silico analysis using TCGA and GTex datasets. We also observed remarkably elevated levels of TOMM22 protein expression in preneoplastic and neoplastic pancreatic lesions, which was associated with stage wise progression of the disease. In model HPAF cells, TOMM22 silencing resulted in decreased growth, migration, and invasion, whereas its ectopic overexpression had the opposite effect in BxPC3 cells. These phenotypic changes were associated with a marked increase in the import of nuclear-encoded (OXPHOS) associated proteins, complex I activity, mitochondrial respiration and ATP production. Furthermore, inhibition of complex I activity in TOMM22 proficient cells delimited the tumorigenic potential and ATP production of PDAC cells, thus, indicating that the tumor promoting effects of TOMM22 overexpression are due to its regulation of mitochondrial protein import and functions. Overall, TOMM22 is overexpressed in PDAC and associated with its progression, as well as plays a significant role in PDAC pathobiology through modulation of mitochondrial protein import and functions.

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