A Multi-Factorial Assessment of Partial Mitochondrial Complex I Impairment in Colorectal Cancer

Abstract

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, yet the metabolic mechanisms that underlie its initiation and progression remain poorly defined. Mitochondrial metabolism, particularly the function of respiratory complex I, has emerged as a key determinant of tumor bioenergetics and signaling. This dissertation investigates how partial complex I dysfunction influences CRC tumor growth and whether the impact of this partial disruption depends on the timing of mitochondrial impairment. Using a combination of human CRC samples, cell-based systems, tumor-derived organoids, and genetically engineered mouse models, this work demonstrates that partial disruption of complex I accelerates CRC tumor growth by inducing metabolic reprogramming that sustains proliferation of cancer cells despite impaired oxidative phosphorylation. Bioenergetic analyses reveal that CRC tissues and models with reduced complex I activity display decreased NADH-linked respiration and diminished ATP synthesis efficiency. Supporting this observation, CRC-related reductions in the mitochondrial proteome where predominantly localized to subunits of complex I. Furthermore, in models of chemically induced colitis, complex I-supported respiration is preferentially reduced, linking inflammatory stress to mitochondrial dysfunction that may predispose the colon to tumorigenesis. Timing-dependent experiments indicate that the stage at which complex I impairment occurs determines its pro-tumorigenic potential, consistent with evolving metabolic dependencies during CRC progression. Collectively, these findings establish that partial, time-specific complex I dysfunction enhances CRC tumor growth by promoting redox imbalance and metabolic rewiring. This work provides new insight into how mitochondrial bioenergetic lesions contribute to CRC pathogenesis and highlights the importance of considering mitochondrial function and treatment timing in the development of metabolic-targeted therapies.