**4. The effect of lifestyle factors on mitochondria function and dynamics**

## **4.1 Exercise and mitochondria**

Traditionally observed at a large, systemic level, research in recent years has begun to investigate the effect of exercise on mitochondrial function and dynamic processes. Furthermore, encouraging results have been observed by analyzing these effects in physiological processes in the brain and pathological conditions such as Alzheimer's disease and Parkinson's disease [98–101]. After old and young mice were subjected to 6 weeks of treadmill exercise, old mice were found to respond positively, showing attenuated activity of coupled complexes I–III of the ETC [99].

Exercise regulates mitochondrial fission and fusion proteins such as Opa1, Mfn2, and Drp1 and enhances mitochondrial biogenesis via upregulation of mitochondrial DNA. This suggests a role for exercise in maintaining a healthy population of mitochondria [98, 101]. In addition, rodents that undergo physical exercise demonstrate improved cognitive and exploratory behaviors along with improved mitochondrial redox homeostasis and mitochondria-mediated brain energy metabolism [102–104].

Exercise has been shown to regulate apoptosis through the regulation of the Bcl-2 family in various models and tissues. As previously discussed, age can have a significant role in mitochondrial dysfunction. A study conducted by Kim et al. investigated how hippocampal neurogenesis and apoptosis were affected by treadmill exercise in young and old-aged rats [105]. Expressions of caspase-3, Bax, Bid, and Bcl-2 were all increased in old mice. After being subjected to treadmill exercise for 30 minutes, once per day for 6 weeks, old rats exhibited further enhancement of Bcl-2 expression, along with decreased expressions of caspase-3, Bax, and Bid. Interestingly, exercise did not impact expressions of Bcl-2, Bax, or caspase-3 in young mice. These results implicate that aerobic exercise may be especially important during aging to exert neuroprotective properties. Aboutaleb et al. examined the effect exercise had on the ratio of Bax/Bcl-2 proteins in hippocampal CA3 cells after ischemia. Ischemic insult led to an increase in caspase-3 and decrease in Bcl-2, thus an increase in Bax/Bcl-2 ratio. However, rats pre-subjected to exercise showed reduced levels of caspase-3 and attenuation of Bax/Bcl-2 ratio [106]. Similar results have been seen in a rodent TBI model, in which treadmill exercise lowered the Bax/ Bcl-2 ratio and decreased the levels of active caspase-3 [107]. Likewise, endurance exercise exerted neuroprotection in PD models by modulation of Mcl-1, Bcl-2, and apoptosis-inducing factor [108]. Although Bcl-2 has primarily been investigated in rodent exercise models, exercise results in a negative regulatory effect on caspase-3 [105–107] which may reduce post-translational cleavage of Bcl-xL supporting neuronal survival [67, 69].

Since the Bcl-2 family proteins are present in the mitochondria throughout all tissue types, it is plausible that protective effects observed in non-neuronal mitochondria are indeed simultaneously occurring in neuronal mitochondria. For example, due to the correlation between diabetes and cardiovascular disease, Cheng et al. examined the relationship between apoptosis, cardiomyocytes, and aerobic exercise in streptozotocin (STZ)-induced diabetic rats. The STZ rats had significantly lower amounts of Bcl-2, Bcl-xL, and p-Bad and higher levels of caspase-3 than controls. However, these levels were all rescued when subjected to aerobic exercise [109]. These results implicate the ability of aerobic exercise to regulate apoptosis and exert cellular protection, even during chronic conditions.

#### **4.2 Non-neurological conditions and mitochondrial consequences**

As chronic diseases such as diabetes and obesity become more prevalent worldwide, research is uncovering the relationship between traditional non-neurological and brain-associated diseases. However, many interventions in studies concerning chronic diseases observe outcomes on a macrolevel and may not consider molecular effects. For these reasons, it is important to uncover how these non-neurological chronic conditions are impacting the mitochondria. By elucidating these

**293**

*Lifestyle Factors, Mitochondrial Dynamics, and Neuroprotection*

activity in the mitochondria of diabetic rats [117].

mitochondrial membrane potential [120–122].

studied regarding efficacy in neuroprotection [123–125].

**4.3 Diet and mitochondria**

mechanisms, this can serve as an additional, albeit perhaps overlooked, means of

Obesity is known to increase the risk of developing diabetes, cardiovascular disease, and neurological conditions. Indeed, obese animal models are often utilized to study insulin resistance. A characteristic of obesity is chronic inflammation and oxidative stress, so it is not surprising that mitochondrial dysfunction occurs throughout the body, including the brain [114]. Specifically, brain mitochondria of obese rats induced via a high-fat diet have repeatedly demonstrated a shift to pro-apoptotic pathways, as shown by elevated Bax expressions, lowered Bcl-2, and a higher Bax/Bcl-2 ratio [118, 119]. The detrimental effects of obesity continue to be demonstrated in the brain by upregulating production of ROS and alteration of

Diet, including intake of specific nutrients and overall encompassing dietary

Treatment of diseases via diet is appealing due to the ability of nutrients to cross the blood brain barriers and ease of accessibility. Specifically, it is important to consider how an individual's overall dietary pattern impacts cellular processes. Dietary patterns, including composition of macronutrients and caloric provision, have been

Caloric restriction has been implicated in the protection against several pathological brain conditions in various animal models such as AD and PD and under conditions of excitotoxicity [126–130]. Caloric restriction has been shown to confer protection from neurodegeneration by improving mitochondrial redox status

patterns, is a driver of maintaining cellular processes throughout the body.

Besides disrupting the uptake of glucose, diabetes can also damage the function, population, and morphology of mitochondria in neurons, potentially contributing to impaired cognition later in life [110–113]. Metabolic pathways that can lead to energy failure in mitochondria as well as prevent antioxidant interception are affected by diabetes. In the diabetic brain, mitochondrial perturbation can result in a lack of neuronal energy that will alter synaptic function and eventually cause the neurons to degenerate [114]. The effect of energy impairments is demonstrated in a cross-sectional study in which adolescents with type 2 diabetes had slower conversion rates of ADP to ATP than obese and lean controls. The explanation for this effect was suspected to be due to decreased blood flow, thus causing alterations in oxygen delivery [115]. Studies have shown that diabetes can modify fission mechanisms in rodent models. Although amounts of Mfn1 and Opa1 remain unchanged during diabetes, Drp1 mRNA is increased. Furthermore, there is an increase of translocation of Drp1 to the mitochondria in diabetes [110, 113]. This increase in translocation is due to GSK3β-mediated phosphorylation at Ser616 of Drp1. The combination of unchanged Mfn1 and Opa1 with increased Drp1 proposes that the disproportion between fission and fusion proteins contributes to mitochondrial dysfunction in rats with diabetes. This was further evident by altered mitochondrial morphology and density. Elevated levels of Drp1 can lead to mitochondrial fragmentation that is conducive to damage in the synapses of neurons, contributing to impairments in learning and memory [116]. Beyond alterations in fission and fusion, decreased ATP production and activity of complex I were observed in the diabetic hippocampus. Moreover, glutathione and ascorbate levels were decreased, suggesting that diabetes impairs mitochondrial antioxidant systems [110]. These results are supported by a study that found decreased coenzyme Q9 and ATPase

*DOI: http://dx.doi.org/10.5772/intechopen.89416*

prevention against brain pathology.

#### *Lifestyle Factors, Mitochondrial Dynamics, and Neuroprotection DOI: http://dx.doi.org/10.5772/intechopen.89416*

*Neuroprotection - New Approaches and Prospects*

processes. Furthermore, encouraging results have been observed by analyzing these effects in physiological processes in the brain and pathological conditions such as Alzheimer's disease and Parkinson's disease [98–101]. After old and young mice were subjected to 6 weeks of treadmill exercise, old mice were found to respond positively, showing attenuated activity of coupled complexes I–III of the ETC [99]. Exercise regulates mitochondrial fission and fusion proteins such as Opa1, Mfn2, and Drp1 and enhances mitochondrial biogenesis via upregulation of mitochondrial DNA. This suggests a role for exercise in maintaining a healthy population of mitochondria [98, 101]. In addition, rodents that undergo physical exercise demonstrate improved cognitive and exploratory behaviors along with improved mitochondrial redox homeostasis and mitochondria-mediated brain energy metabolism [102–104]. Exercise has been shown to regulate apoptosis through the regulation of the Bcl-2 family in various models and tissues. As previously discussed, age can have a significant role in mitochondrial dysfunction. A study conducted by Kim et al. investigated how hippocampal neurogenesis and apoptosis were affected by treadmill exercise in young and old-aged rats [105]. Expressions of caspase-3, Bax, Bid, and Bcl-2 were all increased in old mice. After being subjected to treadmill exercise for 30 minutes, once per day for 6 weeks, old rats exhibited further enhancement of Bcl-2 expression, along with decreased expressions of caspase-3, Bax, and Bid. Interestingly, exercise did not impact expressions of Bcl-2, Bax, or caspase-3 in young mice. These results implicate that aerobic exercise may be especially important during aging to exert neuroprotective properties. Aboutaleb et al. examined the effect exercise had on the ratio of Bax/Bcl-2 proteins in hippocampal CA3 cells after ischemia. Ischemic insult led to an increase in caspase-3 and decrease in Bcl-2, thus an increase in Bax/Bcl-2 ratio. However, rats pre-subjected to exercise showed reduced levels of caspase-3 and attenuation of Bax/Bcl-2 ratio [106]. Similar results have been seen in a rodent TBI model, in which treadmill exercise lowered the Bax/ Bcl-2 ratio and decreased the levels of active caspase-3 [107]. Likewise, endurance exercise exerted neuroprotection in PD models by modulation of Mcl-1, Bcl-2, and apoptosis-inducing factor [108]. Although Bcl-2 has primarily been investigated in rodent exercise models, exercise results in a negative regulatory effect on caspase-3 [105–107] which may reduce post-translational cleavage of Bcl-xL supporting

Since the Bcl-2 family proteins are present in the mitochondria throughout all tissue types, it is plausible that protective effects observed in non-neuronal mitochondria are indeed simultaneously occurring in neuronal mitochondria. For example, due to the correlation between diabetes and cardiovascular disease, Cheng et al. examined the relationship between apoptosis, cardiomyocytes, and aerobic exercise in streptozotocin (STZ)-induced diabetic rats. The STZ rats had significantly lower amounts of Bcl-2, Bcl-xL, and p-Bad and higher levels of caspase-3 than controls. However, these levels were all rescued when subjected to aerobic exercise [109]. These results implicate the ability of aerobic exercise to regulate

As chronic diseases such as diabetes and obesity become more prevalent worldwide, research is uncovering the relationship between traditional non-neurological and brain-associated diseases. However, many interventions in studies concerning chronic diseases observe outcomes on a macrolevel and may not consider molecular effects. For these reasons, it is important to uncover how these non-neurological

apoptosis and exert cellular protection, even during chronic conditions.

chronic conditions are impacting the mitochondria. By elucidating these

**4.2 Non-neurological conditions and mitochondrial consequences**

**292**

neuronal survival [67, 69].

mechanisms, this can serve as an additional, albeit perhaps overlooked, means of prevention against brain pathology.

Besides disrupting the uptake of glucose, diabetes can also damage the function, population, and morphology of mitochondria in neurons, potentially contributing to impaired cognition later in life [110–113]. Metabolic pathways that can lead to energy failure in mitochondria as well as prevent antioxidant interception are affected by diabetes. In the diabetic brain, mitochondrial perturbation can result in a lack of neuronal energy that will alter synaptic function and eventually cause the neurons to degenerate [114]. The effect of energy impairments is demonstrated in a cross-sectional study in which adolescents with type 2 diabetes had slower conversion rates of ADP to ATP than obese and lean controls. The explanation for this effect was suspected to be due to decreased blood flow, thus causing alterations in oxygen delivery [115]. Studies have shown that diabetes can modify fission mechanisms in rodent models. Although amounts of Mfn1 and Opa1 remain unchanged during diabetes, Drp1 mRNA is increased. Furthermore, there is an increase of translocation of Drp1 to the mitochondria in diabetes [110, 113]. This increase in translocation is due to GSK3β-mediated phosphorylation at Ser616 of Drp1. The combination of unchanged Mfn1 and Opa1 with increased Drp1 proposes that the disproportion between fission and fusion proteins contributes to mitochondrial dysfunction in rats with diabetes. This was further evident by altered mitochondrial morphology and density. Elevated levels of Drp1 can lead to mitochondrial fragmentation that is conducive to damage in the synapses of neurons, contributing to impairments in learning and memory [116]. Beyond alterations in fission and fusion, decreased ATP production and activity of complex I were observed in the diabetic hippocampus. Moreover, glutathione and ascorbate levels were decreased, suggesting that diabetes impairs mitochondrial antioxidant systems [110]. These results are supported by a study that found decreased coenzyme Q9 and ATPase activity in the mitochondria of diabetic rats [117].

Obesity is known to increase the risk of developing diabetes, cardiovascular disease, and neurological conditions. Indeed, obese animal models are often utilized to study insulin resistance. A characteristic of obesity is chronic inflammation and oxidative stress, so it is not surprising that mitochondrial dysfunction occurs throughout the body, including the brain [114]. Specifically, brain mitochondria of obese rats induced via a high-fat diet have repeatedly demonstrated a shift to pro-apoptotic pathways, as shown by elevated Bax expressions, lowered Bcl-2, and a higher Bax/Bcl-2 ratio [118, 119]. The detrimental effects of obesity continue to be demonstrated in the brain by upregulating production of ROS and alteration of mitochondrial membrane potential [120–122].

## **4.3 Diet and mitochondria**

Diet, including intake of specific nutrients and overall encompassing dietary patterns, is a driver of maintaining cellular processes throughout the body. Treatment of diseases via diet is appealing due to the ability of nutrients to cross the blood brain barriers and ease of accessibility. Specifically, it is important to consider how an individual's overall dietary pattern impacts cellular processes. Dietary patterns, including composition of macronutrients and caloric provision, have been studied regarding efficacy in neuroprotection [123–125].

Caloric restriction has been implicated in the protection against several pathological brain conditions in various animal models such as AD and PD and under conditions of excitotoxicity [126–130]. Caloric restriction has been shown to confer protection from neurodegeneration by improving mitochondrial redox status

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.

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 regulating autophagy and mitochondrial fission, respectively.

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*Lifestyle Factors, Mitochondrial Dynamics, and Neuroprotection*

treatment that is easily translated from bench to bedside.

Human Environmental Sciences, the University of Alabama.

Katheryn Broman, Abigail U. Davis, Jordan May and Han-A Park\*

\*Address all correspondence to: hpark36@ches.ua.edu

provided the original work is properly cited.

Department of Human Nutrition and Hospitality Management, College of Human

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Environmental Sciences, The University of Alabama, Tuscaloosa, AL, USA

The authors declare no conflict of interest.

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

This research was funded by Summer Research Support by the College of

*DOI: http://dx.doi.org/10.5772/intechopen.89416*

**5. Conclusions**

**Acknowledgements**

**Conflict of interest**

**Author details**
