**5. Conclusions**

*Neuroprotection - New Approaches and Prospects*

by reducing ROS production localized to complex I of the ETC [131]. Recent evidence suggests that caloric restriction may prevent formation of ROS via upregulation of antioxidants such as mitochondrial superoxide dismutase 2 (SOD2) and glutathione [132]. Caloric restriction has also been reported to upregulate antioxidants localized to the plasma membrane such as coenzyme Q10 and α-tocopherol via an increase in redox enzymes that are capable of reducing these molecules back to their antioxidant form [133]. Due to coenzyme Q10's pivotal role as an electron carrier in the ETC, we speculate that caloric restriction may be beneficial to maintain redox balance in the mitochondrial membrane. Additionally, mRNA expressions of Bcl-2 and Bcl-xL were also reported to be upregulated in the ipsilateral cortex region of mice placed on caloric restriction against TBI [134], indicating that caloric restriction may prevent TBI-induced neuronal loss. Furthermore, caloric restriction improves mitochondrial function by enhancing ATP levels in aging mice [135]. Mice placed on caloric restriction for 6 months had increased mitochondrial biogenesis and increased levels of cytochrome c oxidase and citrate synthase activity, enhancing mitochondrial respiration [136]. Caloric restriction may enhance mitochondrial metabolism by also upregulating the activity of complexes I, III, and IV [128]. Interestingly, recent evidence shows that caloric restriction enhances expression of brain-derived neurotrophic factor (BDNF) [137, 138], which has been reported to regulate mitochondrial mobility and enhance presynaptic docking [139]. However, the mechanisms of how caloric restriction mediates BDNF expression are still unclear. Clinical trials in which older adults are placed on caloric restriction consistently yield positive results, such as improved memory and enhanced gray matter [140, 141]. Additionally, caloric restriction attenuated behavioral dysfunction in a model of PD in adult rhesus monkeys [130]. Taken together, these studies point *toward* caloric restriction mediating biological markers of chronic disease such as oxidative stress and supporting mitochondrial function by enhancing ATP metabolism and possibly

lessening clinical symptoms associated with neurodegeneration.

ing autophagy and mitochondrial fission, respectively.

The ketogenic diet, popular for its high-fat and very low carbohydrate pattern, has recently been implicated in protection of the brain through apoptotic pathways. Various mammalian animals placed on the ketogenic diet show decreased rates of apoptotic stimuli in neuronal cells via downregulation of mitochondrial cytochrome c release and active caspase-3 both in seizures [142, 143] and TBI models [144], respectively. The decrease in translocation of cytochrome c from the mitochondria to the cytosol may be through the regulation of Bcl-2. One study found that both a high carbohydrate and a high ketogenic diet upregulate Bcl-2 in cortical neurons after focal cerebral ischemia; however, the ketogenic diet displayed higher upregulation [145], indicating that the ketogenic diet may be more efficient in regulating apoptosis than a high carbohydrate diet. The ketogenic diet may play an additional role in cell death and survival pathways, as it has been noted to protect hippocampal cells from death by preventing the interaction between Bad and Bcl-xL [146]. The ketogenic diet further supports neuronal energy metabolism by maintaining mitochondrial morphology, enhancing biogenesis of mitochondria, and improving mitochondrial respiration [147–151]. After neurotoxic insult, the ketogenic diet enhanced complex I-driven oxygen consumption and prevented loss of complex II–III function, implicating the ketogenic diet's ability to improve the activity of the ETC [147, 149]. Likewise, the ketogenic diet attenuates mitochondrial oxidative stress levels in both in vitro and in vivo model, which prevents energy deficit associated with brain cell damage [147, 149, 151]. Interestingly, the ketogenic diet has also been shown to upregulate Beclin-1 [142] and Drp1 [148], suggesting that the ketogenic diet may be able to control mitochondrial population by regulat-

**294**

Mitochondria are well established in their role with ATP production, apoptosis, ROS homeostasis, and intracellular ion signaling. Research in recent years has recognized that proper execution of these processes is reliant on the mitochondria's dynamic capabilities. In this chapter we have discussed mechanisms of mitochondrial morphology, degradation, and trafficking, as well as the relationship between these processes and pathological brain conditions. Utilizing lifestyle factors, such as exercise and diet, can serve as a neuroprotective strategy by targeting neuronal mitochondrial dynamics. Implementing lifestyle changes serves as an accessible treatment that is easily translated from bench to bedside.
