Differential regulation of mitochondrial complex I and oxidative stress based on metastatic potential of colorectal cancer cells

Abstract

Mitochondria serve a vital role in cellular homeo‑ stasis as they regulate cell proliferation and death pathways, which are attributed to mitochondrial bioenergetics, free radicals and metabolism. Alterations in mitochondrial func‑ tions have been reported in various diseases, including cancer. Colorectal cancer (CRC) is one of the most common metastatic cancer types with high mortality rates. Although mitochon‑ drial oxidative stress has been associated with CRC, its specific mechanism and contribution to metastatic progression remain poorly understood. Therefore, the aims of the present study were to investigate the role of mitochondria in CRC cells with low and high metastatic potential and to evaluate the contri‑ bution of mitochondrial respiratory chain (RC) complexes in oncogenic signaling pathways. The present results demon‑ strated that cell lines with low metastatic potential were resistant to mitochondrial complex I (C‑I)‑mediated oxidative stress, and had C‑I inhibition with impaired mitochondrial functions. These adaptations enabled cells to cope with higher oxidative stress. Conversely, cells with high metastatic poten‑ tial demonstrated functional C‑I with improved mitochondrial function due to coordinated upregulation of mitochondrial biogenesis and metabolic reprogramming. Pharmacological inhibition of C‑I in high metastatic cells resulted in increased sensitivity to cell death and decreased metastatic signaling. The present findings identified the differential regulation of mitochondrial functions in CRC cells, based on CRC meta‑ static potential. Specifically, it was suggested that a functional C‑I is required for high metastatic features of cancer cells, and the role of C‑I could be further examined as a potential target in the development of novel therapies for diagnosing high metastatic cancer types.