Abstract SY22-03: Multifaceted mitochondria in the regulation of chromosome inheritance

Abstract Mitosis, the shortest and most dynamic phase of the cell cycle, entails a complex sequence of events that result in the equal distribution of genetic material to two daughter cells. It has been proposed that mitochondrial respiration increases during mitosis to ensure sufficient ATP for this highly energy-demanding process. However, beyond bioenergetics, how concomitant metabolic changes influence mitotic progression and DNA inheritance remains unclear. To visualize these metabolic changes, we introduce fluorescent-based, genetically encoded reporters into cell lines and human tumor organoids, targeting different cellular compartments to track metabolic and redox dynamics during mitosis with high temporal and subcellular resolution. We observe an increase in ATP production in mitochondria and, notably, an increase in the NAD+/NADH ratio in mitotic chromatin upon nuclear envelope breakdown. Strikingly, disrupting this redox change at mitotic entry alters the epigenetic landscape, leading to a hyperacetylated chromatin state that affects chromatin compaction and Aurora B activity. Importantly, this series of events, initiated by metabolic perturbation, induces mitotic errors that result in genetically distinct daughter cells. Altogether, these findings uncover a novel role for mitochondria in regulating genetic inheritance through NAD(H) redox control, a mechanism with the potential to underlie genomic instability in cancer, where lactate accumulation due to the Warburg effect perturbs redox homeostasis. Citation Format: Maria J. Rodriguez Colman. Multifaceted mitochondria in the regulation of chromosome inheritance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr SY22-03.