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

Mitochondria serve a vital role in cellular homeostasis as they regulate cell proliferation and death pathways, which are attributed to mitochondrial bioenergetics, free radicals and metabolism. Alterations in mitochondrial functions 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 mitochondrial 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 contribution of mitochondrial respiratory chain (RC) complexes in oncogenic signaling pathways. The present results demonstrated 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 potential 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 metastatic 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.

Comparative bioenergetic study of neuronal and muscle mitochondria during aging.

Mitochondrial respiratory chain defects have been associated with various diseases and with normal aging, particularly in tissues with high energy demands, including brain and skeletal muscle. Tissue-specific manifestation of mitochondrial DNA (mtDNA) mutations and mitochondrial dysfunction are hallmarks of mitochondrial diseases although the underlying mechanisms are largely unclear. Previously, we and others have established approaches for transferring mtDNA from muscle and synaptosomes of mice at various ages to cell cultures. In this study, we carried out a comprehensive bioenergetic analysis of cells bearing mitochondria derived from young, middle-aged, and old mouse skeletal muscles and synaptosomes. Significant age-associated alterations in oxidative phosphorylation and regulation during aging were observed in cybrids carrying mitochondria from both skeletal muscle and synaptosomes. Our results also revealed that loss of oxidative phosphorylation capacity may occur at various ages in muscle and brain. These findings indicate the existence of a tissue-specific regulatory mechanism for oxidative phosphorylation.