**2. Mitochondrial dynamics**

*Neuroprotection - New Approaches and Prospects*

postsynaptic vesicles [5].

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

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

It has been well studied that Bcl-2 family of proteins controls neuronal survival

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.

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].

activities; thus Smac/ DIABLO exhibits pro-apoptotic roles [8].

**286**

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 properly execute neurotransmission.
