**2.1 Fission and fusion**

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

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 endocytic vesicles [37].

## **2.2 Mitochondrial trafficking**

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 a longer time [39].

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

**Figure 1.**

*Mitochondrial movement in primary hippocampal neurons. Primary hippocampal neurons were labeled with mitoRFP, a red fluorescent tag that labels mitochondria. Micrographs were taken at 3 and 4 weeks after seeding. Morphology and location of mitochondria change over time.*

motors drive transport in two directions. Movement away from the soma or anterograde movement is conducted by the ATPase family of kinesins, with kinesin-1 being responsible for mitochondrial transport, specifically in neurons [38, 40]. Kinesin-1 consists of heavy chains (KHC) and light chains, with the heavy chains being the driving force that allows kinesin-1 to function as a motor protein [41]. Retrograde movement or movement toward the soma is driven by dynein. However, it is likely that these movements are coordinated rather than competitive toward each other, as it has been demonstrated that inhibiting kinesin-1 in *Drosophila* reduces retrograde movement [42].

Mitochondrial Rho-GTPase, or Miro, is an outer membrane receptor, Ca2+ sensor, and another pertinent regulator of mitochondrial motility due to its ability to anchor kinesin and dynein to the mitochondrial outer membrane [43]. Miro's anchoring role has been extensively studied in anterograde movement in the motor/ adaptor complex formed between KHC and Miro, connected by the protein adaptor milton [44, 45].

Another important component of mitochondria trafficking is stationary docking. Mitochondrial docking is largely mediated by the axonal outer membrane protein syntaphilin (SNPH) and its interaction with microtubules in the cytoskeleton. This is demonstrated in rodent models in which deletion of the SNPH gene results in an increase in mitochondria motility and reduced density, while overexpression of endogenous or exogenous SNPH abolished mobility [46]. Along with decreasing the percentage of immobile mitochondria, loss of SNPH decreases axonal branching in cortical neurons [47]. This effect is comparable to neurons lacking LKB-1 and NUAK1, which is necessary for axonal specification [48]. The removal of either of these kinases leads to a decrease in the number of stationary mitochondria along with decreased branching. However, overexpression of SNPH in the LKB-1 and NUAK1-null neurons rescued these effects. Collectively, this implies that docking of mitochondria is required for axonal branching and growth [47]. Since Bcl-xL is required for neurite outgrowth [49], it is possible that Bcl-xL exerts this effect by interacting with docking proteins such as syntaphilin. However, the exact role of Bcl-xL in docking mechanisms must be further elucidated.

## **3. Alteration of mitochondrial function in brain-associated diseases**

While various brain-associated diseases have different pathophysiologies, there is an underlying similarity that consistently occurs: mitochondrial dysfunction. Throughout these conditions, neurodegeneration is correlated with an energy deficit caused by inefficient operation of the ETC, activation of mitochondria-dependent apoptosis, and accumulation of ROS. In addition, excitotoxicity, which commonly

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*Lifestyle Factors, Mitochondrial Dynamics, and Neuroprotection*

associated conditions and mitochondrial dynamics.

oxidation, and altered antioxidant systems [58].

**3.1 Parkinson's disease**

demand of ATP [61].

and promotion of apoptosis.

occurs during cerebral ischemia and traumatic brain injury, impairs homeostasis of excitatory neurotransmitter glutamate [50–53]. Overstimulation of glutamate receptors further leads to Ca2+ release; because mitochondria are one of the key regulators of Ca2+, excessive influx can consequently lead to mitochondrial dysfunction, altered membrane permeabilization, and subsequent cell death [50, 54–56]. Pathways such as these have been extensively explored in neurological conditions. However, research in the past decade has begun to determine the relationship between brain-

Parkinson's disease (PD) is a common neurodegenerative disease that has detrimental clinical effects including tremors, impaired gait, and stiffness of limbs [57]. These symptoms are often due to PD's hallmark characterization of degeneration of the dopaminergic neurons in the substantia nigra. Individuals with PD are vulnerable to increased ROS production due to reduced complex 1 activity, increased lipid

As several PD-specific proteins impact mitochondrial dynamics, it is possible

that the neurodegeneration that occurs with PD is linked to alterations in fission and fusion [59, 60]. Dopaminergic neurons depleted of Drp1 demonstrated decreased mitochondrial mass, impaired motility, and overall neuron loss. Neurons depleted with Drp1 had less mitochondria in the soma and were almost completely depleted from the axons; by not having mitochondria at axons, this can lead to the neurodegeneration due to energy deficits, as synaptic transmission requires a high

The PINK1/Parkin pathway has been traditionally studied with its roles in mitophagy. Under normal physiological conditions, PINK1 accumulates on the surface of dysfunctional mitochondria to signal Parkin translocation to initiate ubiquitination [62]. However, mutations in PINK1 and Parkin, which have been linked to early onset familial forms of PD, lead to loss of mitochondrial membrane potential, leading to impairment of Parkin's translocation and thus accumulation of dysfunctional mitochondria [63]. Research in recent years has begun to uncover the role of the PINK1/Parkin pathway in mitochondrial transport. Overexpression of PINK1 phosphorylates Miro, targeting it for ubiquitination and subsequent degradation. This results in the dismantling of the motor/adaptor complex, releasing kinesin and milton from the mitochondrial surface, and leads to halting of mitochondrial motility [64]. It is possible that this system may promote neuroprotection by preventing anterograde transport of mitochondria and allowing PINK1 to accumulate on damaged mitochondria to initiate mitophagy [65]. Furthermore, PINK1 may exert neuroprotection due to its interaction with Bcl-xL [66]. It has been shown that PINK1 phosphorylates Bcl-xL at its Ser62; as a result, this prevents N-terminal cleavage of Bcl-xL or formation of ΔN-Bcl-xL, which has been associated with neuronal death [67–69]. However, if altered PINK1 expression occurs as a result of genetic mutation, this may lead to dysregulated mitochondrial transport

The presynaptic protein α-synuclein is a major constituent of Lewy bodies, with mutations in its encoding gene, SNCA, being linked to familial PD [70]. Some amount of α-synuclein can localize to the mitochondria, inducing mitochondrial fragmentation, dysfunction, and downregulation of complex 1 activity, potentially contributing to ROS production [71]. Overexpression of α-synuclein results in cytotoxicity due to decreased Bcl-xL expression and increased Bax expression [72]. Shaltouki's research group recently investigated the role of α-synuclein on

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

occurs during cerebral ischemia and traumatic brain injury, impairs homeostasis of excitatory neurotransmitter glutamate [50–53]. Overstimulation of glutamate receptors further leads to Ca2+ release; because mitochondria are one of the key regulators of Ca2+, excessive influx can consequently lead to mitochondrial dysfunction, altered membrane permeabilization, and subsequent cell death [50, 54–56]. Pathways such as these have been extensively explored in neurological conditions. However, research in the past decade has begun to determine the relationship between brainassociated conditions and mitochondrial dynamics.
