Figure 1. The role of mitochondria in neuroplasticity. Principal mechanisms leading to neuronal impairment and cell death are composed of decreased adenosine-5′-triphosphate (ATP) production, increased production of reactive oxygen and nitrogen species (RONS), initiation of apoptotic processes and impaired calcium homeostasis. Exhaustion of energy supplies and decreased ATP production lead to impairment of ATP-dependent processes and therefore to changed cellular functions. Insufficient function of Na+, K+- ATPases leads to disturbances of ion transmembrane gradients, efflux of K+, and influx of Na+, Cl- and Ca2+. Increased extracellular concentrations of K+ mediate depolarization of membranes and change the functions of amino acids transporters. Voltage-gated ion channels (VGIC) and ligand-dependent calcium channels (LGIC) are activated and mediate increased cytosolic calcium concentrations. Intracellular calcium causes functional changes of amino acid transporters and enhances the increased extracellular concentrations of excitatory amino acid, glutamate especially, and extends neurotoxicity. Increased levels of synaptic glutamate can be mediated by release of glutamate from astrocytes. The activation of ionotropic glutamate receptors leads to higher Ca2+ influx into the cell, which is followed by increased activation of phospholipases, proteases, and endonucleases. For example, activation of phospholipase A2 (PLA2) by calcium releases membrane arachidonic acid (AA), which induces production of superoxide. High intracellular calcium levels cause overload of mitochondrial calcium, increase reactive oxygen species (ROS) production, and inhibit ATP production. Activation of calcium-dependent protein phosphatases (e.g. calcineurin) causes translocation of proapoptotic factor Bad into the mitochondria and triggers apoptosis by sequestration of antiapoptotic factors Bcl-2 and Bcl-xL. Release of cytochrome c (cyt c) and other proapoptotic factors from the intermembrane space of mitochondria induce the formation of apoptosome, and consequently triggers activation of caspases and apoptosis. Apoptosis-inducing factor (AIF) is another factor released by mitochondria. Disengaged AIF is transported into the nucleus and triggers caspases-independent apoptosis. Mitochondria in the brain are also a target of nitric oxide (NO) action. Bax, Bak, Bad, proapoptotic factors of Bcl-2 family; Bcl-2, antiapoptotic factor of Bcl-2 family; BDNF, brain-derived neurotrophic factor; CaM, calmodulin; cAMP, cyclic adenosine monophosphate; CREB, cAMP response element-binding; Δψm, potential on the inner mitochondrial membrane; EAAT, excitatory amino acid transporter; ER, endoplasmic reticulum; Glu, glutamate; MAO, monoamine oxidase; nNOS, neuronal nitric oxide synthase; PKA, protein kinase A; PLC, phospholipase C.
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