**1. Introduction**

Frequently referred to as the "the powerhouse of the cell," the mitochondrion is the key organelle that contributes to neuronal energy and viability through the production of adenosine triphosphate (ATP) via oxidative phosphorylation. During oxidative phosphorylation, electrons from FADH2 or NADH travel across the electron transport chain (ETC) creating an electrical gradient along the inner mitochondrial membrane allowing protons to diffuse through the ATP synthase. This allows the ATP synthase to bind a phosphate group to adenosine diphosphate (ADP) creating ATP. Compared to other metabolic pathways such as fermentation and anaerobic respiration, oxidative phosphorylation is the most efficient process to generate ATP. Energy in the brain is used for overall maintenance of cellular processes, neuronal growth, and axonal branching [1]. However, a majority of the ATP produced is utilized to support one of the neuron's most essential functions, synaptic transmission [2]. For example, the Na+ , K+ -ATPase or the Na+ , K+ -pump is responsible for approximately half of the energy consumed by the brain, through its use of active transport to pump out sodium ions while taking in potassium ions [3].

This pump is essential in neurotransmission through its regulation of membrane potential, cell volume, and intracellular Ca2+ homeostasis [4, 5]. Likewise, exocytosis requires sufficient energy to release neurotransmitters from presynaptic to postsynaptic vesicles [5].

Beyond the mitochondria's role in energy production, it is also a key regulator of apoptotic cell death [6]. Various proteins, such as cytochrome c, reside in the mitochondria and participate in apoptotic pathways. In normal physiological conditions, cytochrome c plays a role as an electron carrier in the ETC. However, during neurotoxic conditions, permeabilization of the mitochondrial membrane occurs, and cytochrome c is released into the cytoplasm. Upon release, cytochrome c binds to apoptotic protease activating factor 1 (Apaf-1) which, in turn, activates caspase-9, forming the apoptosome that then activates downstream caspases leading to cell death [7]. Second mitochondria-derived activator of caspase (Smac)/direct IAP-binding protein with low PI (DIABLO) is also a mitochondrial protein released during apoptosis. The N-terminus of Smac/DIABLO directly interacts with inhibitor of apoptosis proteins (IAPs), a family of proteins that inhibit caspase 3, 7, and 9 activities; thus Smac/ DIABLO exhibits pro-apoptotic roles [8].

It has been well studied that Bcl-2 family of proteins controls neuronal survival or death via regulating apoptotic pathways, i.e., pro-apoptotic proteins versus anti-apoptotic proteins [9]. The presence of at least one of the four Bcl-2 homology (BH) domains influences a Bcl-2 family member's role in apoptosis. Pro-apoptotic Bcl-2 family members include the multidomain homology proteins such as Bax and Bak as well as the BH3-only homology proteins such as Bid, Bim, Bad, PUMA, and NOXA. These pro-apoptotic Bcl-2 proteins enhance mitochondrial membrane permeabilization resulting in subsequent release of cytochrome c [10–14].

Anti-apoptotic proteins of the Bcl-2 family include Bcl-2, Bcl-xL, Bcl-w, Mcl-1, and Bfl-1. These proteins contain the BH4 homology, which is essential for antiapoptotic functionality. Both Bcl-2 and Bcl-xL antagonize pro-apoptotic members to prevent apoptosis [15, 16]; for instance, Bcl-xL targets Bak, preventing its oligomerization and inhibiting it from damaging the mitochondrial outer membrane [17]. Similarly, the C-terminal of Bcl-xL binds to the BH3 domain of Bax, resulting in retro-translocation-activated Bax. [18]. Protein-protein binding is further demonstrated with additional members of Bcl-2 family. These observations suggest that the Bcl-2 family's role in mediating apoptosis and mitochondrial permeabilization is largely influenced by dynamic protein-protein interactions with each other [19–21].

The mitochondrion is also responsible for the production of reactive oxygen species (ROS), namely, superoxide and hydrogen peroxide, at Complex I and III of the ETC [22]. This occurs as a result of electron leakage from the complexes, which then allows oxygen to react [23]. Due to the high energy demands required by neuronal mitochondria, this results in increased ROS generation. Increased ROS activity contributes to lipid peroxidation, causing disruption of the hydrophobic interaction between cytochrome c and cardiolipin, thus releasing cytochrome c [24]. Furthermore, the brain is particularly susceptible to oxidative damage due to its composition of high lipid content. Indeed, ROS play a significant role in the regulation of cell death; however, ROS have recently been reported to induce DNA demethylation via 8-oxoguanine DNA glycosylase-1 (OGG1) [25]. As a result, DNA demethylation induces activation of the reelin gene [26], which has been implicated in enhancing synaptic plasticity by inducing long-term potentiation (LTP) [27], thus indicating that normal levels of ROS may play a role in supporting LTP. Additionally, elimination of ROS negatively impacted neural stem cell proliferation in hippocampal cells indicating that homeostatic levels of ROS may possibly be involved in cell proliferation during growth and development [28]; however additional information is needed in order to elucidate the mechanism behind this.

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*Lifestyle Factors, Mitochondrial Dynamics, and Neuroprotection*

Mitochondria were previously thought of as static organelles. Due to advances in molecular biotechnologies, it has been revealed that mitochondria are indeed very dynamic; mitochondria undergo fission and fusion, can vary in morphology, and achieve intracellular movement. Precise execution of these processes is especially vital for proper ATP production, apoptosis, and ROS homeostasis in neurons to

Fission and fusion are integral processes of cellular homeostasis that maintain proper mitochondrial morphology and turnover. Both are mediated by GTPases in the dynamin family, with rates of occurrence depending on changes in metabolic demands. Undoubtedly, fission is essential for dividing cells in order to maintain an adequate number of mitochondria; however, even in nonproliferating neurons, fission is necessary for cell survival [29]. Dynamin-related protein 1 (Drp1) is the primary GTPase that mediates fission, with its activity controlled by phosphorylation via kinases, primarily on two serine residues. Specifically, phosphorylation at Ser616 promotes fission, while phosphorylation at Ser637 inhibits fission, so balance of Drp1 phosphorylation is crucial for proper fission functionality [30]. Impairment in Drp1 leads to alterations in mitochondrial distribution, with mitochondria accumulation occurring at the soma and reduced density in the dendrites. Conversely, Drp1 overexpression yields an increase in dendritic mitochondria [31]. Hippocampal neurons lacking Drp1 display compromised function of axonal mitochondria due to the inability to maintain ATP levels, recycling at synapses [32]. Prominent regulators of fusion include mitofusion 1 and 2 (Mfn1 and Mfn2, respectively) and optic protein atrophy 1 (Opa1). Mitofusion proteins mediate the outer membrane, while Opa1 regulates the inner membrane; however, both work in

Both fission and fusion are enhanced by Bcl-xL, with fission being induced in a Drp1-dependent manner [35]. This is conclusive with a previous study demonstrating the direct interaction of Bcl-xL with Drp1, initiating Drp1-dependent synapse formation in hippocampal cells [36]. When investigated further, this Bcl-xL-Drp1 complex was found to be necessary for presynaptic plasticity by regulating endo-

Trafficking, mobility, and docking are intertwining processes that are vital to ensure neurons are equipped with the proper distribution and recycling of mitochondria at axons and synapses throughout the cell's life span. **Figure 1** demonstrates how mitochondria are motile and change morphology in primary hippocampal cells. Mitochondrial trafficking is mediated by intracellular signaling, physiological events, and alterations in metabolic demands. Approximately 70% of mitochondria are stationary, with the remaining 30% motile [38].

Furthermore, five distinct mitochondria motility patterns have been described by Sun's research group: stationary outside of synapses, docking at synapses, passing though synapses, pausing at synapses for a short amount of time, and pausing for

Mechanisms of mitochondrial movement and transport are overall influenced by the polarity of axons, with the positive end directed toward the soma and the negative at the tips. Utilizing this consistent axonal polarity is how microtubule

coordination in a two-step process to carry out fusion [33, 34].

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

**2. Mitochondrial dynamics**

properly execute neurotransmission.

**2.1 Fission and fusion**

cytic vesicles [37].

a longer time [39].

**2.2 Mitochondrial trafficking**
