Abstract B013: Mitochondrial dysfunction reprograms aggressive prostate cancer metabolism

Abstract Background: Mitochondrial dysfunction is increasingly recognized as a central driver of metabolic reprogramming in aggressive prostate cancer, yet the mechanistic links between impaired oxidative metabolism and tumor progression are poorly understood. We have previously shown that defects in mitochondrial respiration force a shift toward glycolysis and lactate production that fuels proliferation in prostate cancer cells. We now aim to further characterize metabolic adaptations in prostate cancer progression and identify novel mitochondrial vulnerabilities for precision therapies. Methods: We performed studies using human prostate cancer cells and new genetically engineered mouse models (GEMMs). To identify mitochondrial dysfunction-induced metabolic changes that occur in prostate cancer, we conducted preliminary targeted metabolomics and gene expression analyses in prostate cancer cells with impaired mitochondria. Results: We developed a new GEMM of prostate cancer that accumulates mitochondrial genomic alterations with age, leading to mitochondrial dysfunction. These GEMMs exhibited decreased oxidative phosphorylation activity, increased intratumoral lactate production, and an accelerated prostate cancer phenotype. Targeted metabolomics in mitochondrial-impaired prostate cancer cells validated the increased accumulation of lactate and revealed additional metabolomic dysregulated pathways, such as those involved in lipogenesis and glutathione metabolism. Furthermore, preliminary gene expression analysis of prostate tumors from our novel GEMMs showed upregulation of genes associated with enhanced tumorigenesis and metabolic remodeling. Conclusions: Together, these findings demonstrate that prostatic mitochondrial dysfunction can drive a metabolic shift characterized by enhanced glycolysis and broader dysregulation of redox pathways. Thus, mitochondrial dysfunction establishes a pro-tumorigenic metabolic state that accelerates prostate cancer progression. Ongoing work in the lab is focused on assessing the therapeutic potential of targeting glycolytic and other novel metabolic pathways is the context of mitochondrial dysfunction in aggressive prostate cancer. Citation Format: Jessica Damanski, Theresa Dansu, Alexandros Papachristodoulou. Mitochondrial dysfunction reprograms aggressive prostate cancer metabolism [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl):Abstract nr B013.