*2.3. Cancer, Mitochondria, and Inflammation*

Mitochondria are responsible for cellular energy production by changing adenosine diphosphate (ADP) into adenosine triphosphate (ATP) through aerobic respiration. This conversion occurs in a series of redox reactions in the electron-transport chain-enzyme compounds, labeled complex I–IV. Changes in any of these complexes lead to changes in energy output. Hence, dysfunction in mitochondria and in their DNA (mtDNA) creates reduced cellular energy, which has been linked with neurologic symptoms [27]. Mitochondria are especially vulnerable to oxidative stress, a disturbed balance between reactive oxygen species (ROS), and antioxidants. In turn, mitochondrial dysfunction can lead to ROS overproduction, inducing a downward spiral in cellular functioning [28]. Cancer treatment, inflammation, and stress can all affect mitochondrial function by increasing ROS levels, thereby destroying mitochondria [29]. For example, radiation therapy was shown to increase oxidative stress markers in breast cancer patients with severe acute skin reactions to radiation. In another example, chemo-radiation seemed to normalize tumor-related changes in mtDNA expression in the liver of a rodent model of head and neck cancer, while causing severe changes in mtDNA expression in the brain [30]. This suggests that cancer treatment specifically affects cellular energy production in the CNS. In addition, Lacourt and Heijnen [31] argued that mitochondrial dysfunction is the mechanism leading to neurotoxic symptoms. Both inflammation and stress hormones, as well as cancer treatment, can promote mitochondrial dysfunction, resulting in reduced cellular energy. It should be noted that during cancer many disruptions occur in the physiological functioning of brain areas controlling energy homeostasis [31]. In particular, increased hypothalamic expression and release of mediators of neural inflammation play a major role in this process [2].

In summary, mitochondrial dysfunction may be a final common outcome of cancer, cancer therapy, inflammation, ROS, and stress that leads to neurotoxic symptoms. Mitochondria-protecting drugs preventing cancer therapy-related toxicities may point to promising avenues for treatment of neuro-toxicities in cancer patients. Establishment of these drugs in clinical settings, in parallel to the early implementation of stress-reduction interventions shortly after diagnosis, should be considered to prevent the long-term neurotoxic symptoms that plague so many cancer survivors.
