Mitochondrial Metabolic Reprogramming and DNA Damage in Arsenic Carcinogenesis

Mitochondrial metabolism is a key to fueling hyperproliferation during tumor development, in terms of the production of both energy and anabolic precursors. Reprogramming of cellular metabolic networks such as those induced by mitochondrial fumarate hydratase or succinate dehydrogenase mutations is known to induce malignancy in human kidneys (1-3). Aberrations in the Krebs cycle functioning can also lead to excess ROS production by the respiratory electron transport chain, which can be crucial to tumorigenesis (4-7). Moreover, nuclear and mitochondrial (Mt) DNA damages associated with such oxidative stress, have been hypothesized to be an important vehicle for mediating human carcinogenesis (7-9). However, the mechanistic link from the reprogramming of Mt metabolism to human cancer development via Mt DNA damages and defective repair pathway(s) is not well-understood, particularly in the context of environmental insults such as arsenic exposure. Even less is known about how Mt dysfunctions and DNA damages interact with the nuclear and cytoplasmic processes to elicit malignant transformations of human cells. As an environmental carcinogen, arsenic has been demonstrated to alter Mt enzyme activities (10, 11), induce DNA damages (12), and disrupt DNA repair mechanisms (14) in mammalian cells, which make arsenic exposure an excellent system to gain mechanistic understanding on the interplay of Mt and cellular metabolic networks with Mt and nuclear DNA damages during environmental carcinogenesis.