Abstract LB126: Functional limitations in respiratory complex I underlie mitochondrial bioenergetics in human colorectal adenocarcinoma

Typified by oxidative phosphorylation (OXPHOS), mitochondria catalyze a wide variety of cellular processes now understood to be critical for malignant growth. As such, there is considerable interest in targeting mitochondrial OXPHOS in cancer. The present project was based on the premise that the development of efficacious mitochondrial-targeted anti-cancer compounds requires answering two fundamental questions: 1) is mitochondrial bioenergetics in fact different between cancer and non-cancer cells? and 2) If so, what are the underlying mechanisms? To address these questions, we developed a methodological workflow designed to integrate in vitro functional readouts of mitochondrial flux with mass-spectrometry-based proteomics. This allowed us to directly quantitate both total respiratory capacity and OXPHOS kinetics on a per mitochondrion basis. Experiments were performed in isolated mitochondria prepared from freshly resected human colorectal adenocarcinomas (COAD). Relative to adjacent normal colonic mucosa, tumor mitochondria consistently presented with partial disruptions in respiratory complex I (CI). Surprisingly, CI functional limitations did not impair absolute oxidative flux. Instead, the tumor mitochondrial network displayed clear evidence of intrinsic remodeling. Such remodeling maintained respiratory competence at the expense of decreased oxidative ATP synthesis (i.e., OXPHOS inefficiency or increased ‘uncoupling’). Given recent findings demonstrating that mitochondrial OXPHOS is dispensable for tumor growth, our data raise the intriguing possibility that the requirement for mitochondria in COAD may have little to do with oxidative ATP production, but instead reflect a requirement for accelerated mitochondrial flux to support other aspects of anabolic growth (e.g., extracellular nutrient uptake, NAD+ regeneration, nucleotide synthesis). In this respect, rather than functioning as energy producers, COAD mitochondria may primarily function as ‘energy sinks’. Citation Format: Ilya Boykov, McLane M. Montgomery, James T. Hagen, Hannah S. Coalson, Kelsey H. Fisher-Wellman. Functional limitations in respiratory complex I underlie mitochondrial bioenergetics in human colorectal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB126.