Mitochondrial Metabolism in Pancreatic Ductal Adenocarcinoma: From Mechanism-Based Perspectives to Therapy

SIMPLE SUMMARY: In cancer therapy, mitochondrial metabolism has emerged as a particularly attractive target, especially for malignancies such as pancreatic ductal adeno carcinoma (PDAC) that are resistant to treatment. Along with other treatment approaches, including targeting glutamine and fatty acid metabolism and inhibiting the tricarboxylic acid (TCA) cycle precursors, mitochondrial oxidative phosphorylation (OXPHOS) is still a key target in cancer therapy. To the advantage of PDAC patients, innovative and more effective therapeutics will be possible with a greater understanding of how pancreatic cancer cells control mitochondrial metabolism, and their role in PDAC progression through modulating cellular dynamics, bioenergetics, immune education, and retrograde signaling. ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC), the fourteenth most common malignancy, is a major contributor to cancer-related death with the utmost case fatality rate among all malignancies. Functional mitochondria, regardless of their complex ecosystem relative to normal cells, are essential in PDAC progression. Tumor cells’ potential to produce ATP as energy, despite retaining the redox potential optimum, and allocating materials for biosynthetic activities that are crucial for cell growth, survival, and proliferation, are assisted by mitochondria. The polyclonal tumor cells with different metabolic profiles may add to carcinogenesis through inter-metabolic coupling. Cancer cells frequently possess alterations in the mitochondrial genome, although they do not hinder metabolism; alternatively, they change bioenergetics. This can further impart retrograde signaling, educate cell signaling, epigenetic modifications, chromatin structures, and transcription machinery, and ultimately satisfy cancer cellular and nuclear demands. To maximize the tumor microenvironment (TME), tumor cells remodel nearby stromal cells and extracellular matrix. These changes initiate polyclonality, which is crucial for growth, stress response, and metastasis. Here, we evaluate all the intrinsic and extrinsic pathways drawn by mitochondria in carcinogenesis, emphasizing the perspectives of mitochondrial metabolism in PDAC progression and treatment.