Traditionally known as the main cell producers of energy currency in the form of ATP, mitochondria are the most studied cellular organelles due to their structural and functional complexity and their plethora of crucial tasks, such as the regulation of calcium homeostasis, the maintenance of redox balance, the generation of bioactive metabolites, the initiation of apoptosis and the regulation of epigenetics, to cite only a few ^[1][2][1,2].

Mitochondria are also considered important metabolic hubs for their peculiar ability to integrate several signaling networks and metabolic pathways to control cellular functions. However, they are themselves regulated from several cellular effectors, including specific kinases and transcription factors, to reach the best efficiency in producing energy in the form of ATP through the oxidative phosphorylation (OXPHOS) process, through movement inside and outside the cells to reach specific districts, and through performing their own de novo synthesis or clearance. These complex processes, named mitochondrial bioenergetics, dynamics, biogenesis and mitophagy, always take place in response to cellular energy demands ^[3][4][5][3,4,5]. For these reasons, mitochondria numbers and locations depend on tissue/organ metabolic requests.

The brain is the organ with the highest energy requirement, consuming up to 20% of all bodily energy, which takes place 10 times faster than the rest of the body per gram ^[6][7][6,7]. Recently, Bülow and colleagues [8] have estimated that the human brain burns five orders of magnitude more energy than that produced by the sun per unit of mass, reaching a peak of oxygen and glucose consumption to produce ATP around five years of age. Indeed, a child’s brain consumes about 50% of the body’s energy cost that it needs for development and plasticity [9]. Neurons are responsible for a large part of the energy consumption of the brain that is necessary for the maintenance of the dynamics of the actin cytoskeleton and the complex formation of synapses. Astrocytes also sustain the bulk of the metabolic weight in order to control the interstitial fluid composition, to store energy in the form of glycogen, to supply neurons with fuel sources and metabolites for biosynthesis and to recycle neurotransmitters, oxidation products and other metabolic waste products ^[9][10][9,10].

Neurogenesis is the process of transformation of neural stem cells into actively proliferating progenitor cells that, in the final stage, differentiate into mature new neurons ^[11][12][58,59]. Neural stem cells (NSCs) are a population of pluripotent cells in the nervous system that give rise, through the intermediate neuron progenitor cells (NPCs) and glia progenitor cells (GPCs), to neurons and glial cells, including oligodendrocytes and astrocytes ^[13][60]. Importantly, mammalian NSCs may be present not only during embryonic brain development ^[14][61], but also in the neonatal and adult brain ^[15][16][62,63].

For a long time, it was believed that the neural stem cell pool was almost totally depleted during the perinatal phase, leading to an arrest of neurogenesis in the early stages of neonatal life. Though this is certainly true for many brain regions, neurogenesis persists into adulthood in specific areas of the mammalian brain: the subependymal zone of the lateral ventricle (SEZ) of the olfactory bulb and the subgranular zone (SGZ) of the dentate gyrus of the hippocampus ^[17][18][19][64,65,66]. However, the extent to which neurogenesis occurs in human adulthood still remains an object of discussion ^[20][21][22][67,68,69]. New evidence reports that neurogenesis may also be supported outside the classical neurogenic niches in other brain regions of the adult mammalian brain, including the hypothalamus, striatum, substantia nigra, cortex and amygdala (for references, see ^[23][70]).

In the process of generating neurons, the programming of energy metabolism undergoes critical changes. The processes of neuronal proliferation/differentiation and neuronal activity require a significant energy expenditure. Mitochondria are important for the regulation of NPCs during the process of neurogenesis. Neural stem cells rely on glycolysis to meet their energy demands ^[24][71]. Apart from their glycolytic profile, NSCs have immature fragmented mitochondria characterized by a spherical ultrastructure with poorly matured cristae and few copies of mitochondrial DNA ^[25][72]. As NSCs differentiate into intermediate progenitor cells (IPCs) and neural progenitor cells (NPSs), their energy metabolism relies in part on OXPHOS, reducing the contribution from glycolytic metabolism and lactate production ^{[26][27][28][29]}[73,74,75,76]. Once mature neurons form, they rely completely on OXPHOS-dependent energy metabolism to perform neuronal activities ^[26][30][73,77]. During gliogenesis, the process by which NSCs differentiate into astrocytes and oligodendrocytes through the glia progenitor cells (GPCs), mitochondria do not complete the maturation processes. For example, MRC is not organized into supramolecular complexes, and they remain poor energy producers ^[31][78].

Zheng et al. investigated the metabolism switch from anaerobic glycolysis in neural progenitor cells to OXPHOS in mature neurons, indicating that this metabolic shift is essential for neuronal differentiation and matured neuron formation, and it is a critical process in ensuring energy support for neurogenesis ^[32][79]. The starting point of the metabolic switch occurs through the gene expression induction of PGC-1α, the master regulator of mitochondrial biogenesis ^[33][80], and an increase in the synthesis of MRC complexes’ subunits ^[18][65]. Mitochondrial mass increases to sustain the MRC machinery, in association with OXPHOS required for neuronal differentiation ^[34][35][81,82]. During neurogenesis, in order to acquire an OXPHOS metabolic profile, mitochondria increase in number and undergo structural changes to assume an elongated morphology in neurons ^{[32][36][37][38]}[79,83,84,85]. Mitochondrial dynamics also regulate the activation of neurogenesis in NSC-derived NPCs ^[39][86].

Disturbances in mitochondrial biogenesis and OXPHOS during brain development prevent the metabolic switch from glycolysis to OXPHOS that is strictly required to initiate the process of neurogenesis (for refs., see reviews ^{[26][37][40][41]}[73,84,87,88]). Defective OXPHOS bioenergetics or dysfunctions in the regulation of mitochondrial biogenesis and dynamics could compromise neurogenesis and the physiological establishment of neuronal function.

3. Critical Roles of Brain Mitochondria as Master Regulators of Neuronal Plasticity and Central Hubs of Synaptic Modulation

The maintenance and regulation of cellular energy metabolism is a critical challenge for the nervous system. The brain’s metabolic balance is finely controlled by the involvement of a close metabolic integration between neurons and glia, which together form an integrated metabolic unit to meet energy needs of neural circuits ^[42][43][44][32,48,89]. The metabolic cost of performing and sustaining basal neural functions is enormously high and requires functioning mitochondria. For instance, a single neuron can contain thousands of mitochondria ^[45][90], whose function is very crucial to sustain neuronal physiology. In the brain, mitochondria are essential for cell growth ^[39][86], neurotransmission ^[46][91], the maintenance of cell membrane ion gradients ^[47][92] and synaptic pruning ^[48][93]. Mitochondrial bioenergetics critically sustain numerous ATP-dependent processes that allow neurons to function and respond adaptively to environmental challenges in the process known as neuroplasticity ^[49][50][94,95]. Neuroplasticity is defined as the ability of the brain to undergo a series of adaptive changes in the structure and function of nervous cells in response to physiological or pathological perturbations ^[51][96]. Examples of neuroplasticity include the growth of axons or dendrites, the formation of synapses, the consolidation of synapses in response to repeated nerve impulses and neurogenesis. In addition to neurons, glial cells play important roles in neuroplasticity by producing soluble and surface-bound factors that impact neurite outgrowth, synaptic activity and cell survival ^[52][53][25,97]. Two significant examples of neuroplasticity are long-term potentiation (LTP) and long-term depression (LTD), present in neuronal synapses in response to rapid repeated stimulation ^[54][98]. LTP is a form of activity-dependent plasticity resulting in a persistent enhancement of synaptic transmission, whereas LTD consists of a decrease in the efficacy of a synapse as a result of a particular type of stimulation. LTP is also considered to be the cellular mechanism of learning and memory ^[55][56][99,100]. Several studies have documented that changes in mitochondria occur during synaptic activation and LTP ^[56][100]. For example, during LTP, mitochondrial energy production undergoes changes ^[57][101], mitochondrial calcium pump activity increases ^[58][102], and mitochondrial gene expression results are enhanced ^[59][103]. Mitochondria are highly mobile and move rapidly within and between subcellular compartments of the neurons involved in neuroplasticity ^[60][104]. Mitochondria are mostly located along the length of axons and in both the pre- and post-synaptic terminals, providing the energy necessary for the activity of these specialized neuronal compartments. At the dendritic level, they are principally present in dendritic extensions and less frequently associated with spines ^[61][62][105,106]. Mitochondria undergo highly coordinated processes of fission and fusion ^[63][107], responding to the activation of neurotransmitters and growth factor receptors ^[64][108]. Local translation in neurons is fueled by mitochondria that support neuronal plasticity in dendrites and axons, with the mitochondrial compartments able to function as a local energy supply for synaptic translation ^[65][109]. Mitochondrial biogenesis occurs locally to maintain the functional activity of mitochondria in axons and dendrites, indicating that local mitochondrial protein production plays an essential role in synaptic functions ^[66][110]. The biogenesis of mitochondria and their movement along the axon is particularly important because the axon grows much faster and longer than the dendrites, therefore requiring more energy to sustain its rapid growth. As synapses are formed, the number of mitochondria increases, and synaptic activity influences the distribution of mitochondria along the length of the dendrites and axons, in the presynaptic terminals and at the base of the dendritic spines ^[67][111]. Synaptic activity affects the positioning of mitochondria at the base of dendritic spines, where they play an important role in the structural plasticity of the spines ^[46][91]. The biogenesis of neuronal mitochondria usually takes place in the cell body, from which the mitochondria form a dynamic network that is distributed in the various compartments of neurons ^[68][112]. However, axonal mitochondria are much more dynamic than the mitochondria present in dendrites ^[69][70][113,114]. They are highly mobile, and their movement can occur in both anterograde and retrograde directions ^[71][115]. Recent studies have revealed that the dynamic nature of mitochondria can go beyond neuron boundaries [4]. Indeed, mitochondria can translocate between neurons through neural vesicles called exosomes or nano-tunnels; this accounts for the further signaling role of mitochondria as mediators of communication between neurons. As far as transport of axonal mitochondria, they are carried out to the synapse by the motor proteins kinesin and dynein, respectively, which carry their mitochondrial cargo along microtubule tracks ^[72][116]. Mitochondria in neurons can be more present and concentrated in neuronal districts with major metabolic energy needs, such as growth cones and/or pre- and post-synaptic spaces ^[73][117]. The transport of mitochondria along the neurite is a highly regulated process, and the activity of mitochondria in the synapses allows for the integration of different signals; thus, mitochondria are key players in the modulation of synaptic stimulation ^[74][118]. Mitochondria clustered at the synaptic level constitute a discrete mitochondrial pool distinct from non-synaptic neuronal mitochondria, exhibiting different morphological and proteomic features and an increased vulnerability to oxidative damage (for references, see ^[74][118]). Different metabolic energy requirements are linked to the heterogeneity among subcellular compartments in different brain districts ^[75][119], indicating that neuronal mitochondria may be subjected to different processes of regulation based on the neuronal compartment and depending on the brain area.