The generation of new neurons (neurogenesis) from neuronal stem cells (NSCs) is fundamental to neurodevelopment and in the adult brain. NSCs are responsible for brain development in the embryo and persist in the adult brain where they localise primarily in two regions: the subventricular zone (SVZ) of the lateral ventricles, and the subgranular zone (SGZ) of the hippocampal dentate gyrus (1, 2). Newborn neurons from these regions are incorporated in the olfactory bulb and hippocampus, respectively, and support lasting network adaptations to cognitive stimuli (3). Adult hippocampal neurogenesis reinforces cognitive processes including learning and memory (4), modulation of existing memories (5), and the encoding of temporal information (6), whereas olfactory neurogenesis is implicated in the regulation of sensory experience (7).

The development and regeneration of most mammalian tissues depends on a local supply of stem cells contained within a tissue-specific niche. In recent years, mitochondria have emerged as key regulators of stem cell function, strongly impacting stem cell fate decisions, encompassing the decision to self-renew or differentiate. Mitochondria are known as the powerhouse of the eukaryotic cell, generating energy in the form of ATP. Yet mitochondria carry out a wide array of functions, ranging from metabolite and redox signaling to the regulation of nuclear gene expression and epigenetics (8, 9). Mitochondrial functions do vary, however, between different cell types, such as cancer cells, stem cells or postmitotic cells.

In this review, I am introducing this new and exciting research field, which bridges mitochondrial metabolism, neural stem cells and cognitive function. I will describe how mitochondria regulate NSC function and cognition, and how they may be targeted with stem cell-based therapies or other interventions to improve cognitive function.

Mitochondrial Function

Mitochondria are specialised, membrane-enclosed organelles producing most of the ATP that empowers life processes in eukaryotic cells. They occur in virtually all cells of animals, plants and fungi, and they burn food molecules to produce ATP by oxidative phosphorylation (OXPHOS). A second type of energy-converting organelle is represented by chloroplasts, which occur only in plants and green algae. They harness solar energy to produce ATP by photosynthesis. The energy-converting organelles in present-day eukaryotes originate from prokaryotic cells that were endocytosed during the evolution of eukaryotes. Mitochondria are enclosed by an inner and outer mitochondrial membrane separated by an intermembrane space. The inner mitochondrial membrane forms invaginations and sac-like structures called cristae that extend in the mitochondrial matrix (10). Without mitochondria, present-day animal cells would have to generate all of their ATP through anaerobic glycolysis, which oxidates glucose only partially, converting it to pyruvate. In mitochondria, the oxidation is completed: pyruvate is ultimately oxidised by O2 to CO2 and H2O, extracting 15 times more ATP from a sugar than glycolysis alone. Upon import into the mitochondria, pyruvate is converted to acetyl-CoA and enters the tricarboxylic acid cycle (TCA) or the Krebs cycle. The FADH2 and NADH reducing equivalents generated in the TCA cycle donate their high-energy electrons to components of the electron-transport-chain (ETC) embedded in the inner mitochondrial membrane. The passing of these electrons through the ETC chain generates an electrochemical gradient across the membrane which is used by an ATP synthase to generate ATP (10).

Through their functions in energy production and cell signaling, mitochondria are indispensable for the viability of the majority of eukaryotic cells. Proper mitochondrial functionality depends on the stability of mitochondrial DNA (mtDNA) and on a balanced mitochondrial dynamics. The mitochondrial genome houses 13 genes coding for components of the ETC. Hence, mtDNA mutations lead to energy deficits and reactive oxygen species (ROS) generation. Mitochondria are highly dynamic organelles, constantly undergoing fusion and fission events. By doing so, mitochondria continually recycle damaged proteins, promote mtDNA complementation and regulate metabolic homeostasis (11).

Mitochondria and Stem Cell Function

Beyond generation of ATP, recent studies present mitochondria as key players regulating stem cell signaling events and epigenetics. This realisation came as a surprise, considering that the majority of stem cell populations exhibit a highly glycolytic metabolism, with little to no reliance on mitochondrial oxidative phosphorylation (OXPHOS) for ATP production (12). Stem cell mitochondria do actually maintain their capacity to generate ATP through OXPHOS, but they are actively suppressed by several mechanisms from doing so (9, 13, 14). Furthermore, it is well known that disruption of mitochondrial function leads to stem cell abnormalities (15, 16).

Mitochondria function as signaling centres regulating stem cell function. One mechanism by which mitochondria impact stem cell function is by regulating the physiological levels of ROS. A low level of ROS is prerequisite to stem cell maintenance, whereas an increase in ROS levels alters gene expression profiles and promotes stem cell differentiation (17-19). A second mechanism of mitochondrial stem cell regulation depends on intermediate metabolites of the TCA cycle. For example, alpha-ketoglutarate (aKG) can induce DNA and histone demethylation, whereas acetyl-CoA promotes histone acetylation (20, 21). Finally, mitochondria regulate the glycolytic versus oxidative state of the cell and thereby the NAD+ to NADH ratio, which in turn impact the sirtuin (SIRT) family of NAD+ dependent deacetylase enzymes. Generally, decreased NAD+ and SIRT levels promote stem cell differentiation (22, 23). A body of evidence points therefore to mitochondria as major stem cell regulators and key therapeutic targets in the adult brain.

Mitochondria in Neurodevelopment

Brain development relies on constant production of new neurons from NSCs. This process, called neurogenesis, starts with the commitment of NSCs and ends with the terminal differentiation of neural progenitor cells (NPCs) into neurons. The differentiation of NSCs to postmitotic neurons is accompanied by a progressive metabolic shift, from a predominantly glycolytic metabolism in NSCs to one that is highly dependent on mitochondrial OXPHOS in postmitotic neurons (11, 24-26). This metabolic shift not only alters the way by which ATP is generated but is also a vital aspect of cell cycle regulation and proper neuronal differentiation (19, 27).

Apart from metabolical changes, mitochondria also undergo morphological changes during neuronal differentiation (11, 24). Changes in mitochondrial morphology have been shown to direct metabolic changes and NSC fate decisions during neurodevelopment and in the adult brain (11, 28). Mitochondria change their shape, being more elongated within the uncommitted population of NSCs, fragmenting as NSCs commit to a progenitor fate, and finally re-elongating as NPCs differentiate into neurons. Mitochondrial fragmentation promotes NSC commitment to neuronal differentiation by changing nuclear gene expression profiles. This retrograde mitochondria-to-nuclear signaling is mediated by a physiological increase in mitochondrial ROS levels (11). This increase in mitochondrial ROS stabilises the NRF2 master redox regulator which translocates to the nucleus and promotes expression of genes that activate differentiation and suppress self-renewal (11). Cell cycle exit and terminal differentiation of the resulting NPCs into postmitotic neurons are also dependent on functional mitochondria (29).

As central regulators of NSC fate decisions, mitochondria are fundamental for brain development. This view is reinforced by the numerous neurodevelopment disorders arising from aberrant mitochondrial fragmentation, and by the many mitochondrial disorders that manifest in the CNS as cognitive dysfunction and lead to behavioural abnormalities (30). Mitochondrial disorders are characterised by mutations in mtDNA or nuclear DNA that affect the respiratory chain, and often manifest as cognitive impairments, stroke-like episodes and progressive dementia (31). Progressive accumulation of mtDNA mutations may also be an important factor for the cognitive decline over the course of aging (32, 33). It remains to be elucidated whether these neurological manifestations are due to abnormal NSC fate decisions and impaired neurogenesis.

Mitochondria in Adult Neurogenesis

Mitochondrial Dysfunction and Ageing

The metabolic shift that accompanies NSC self-renewal and differentiation during development is maintained in the adult brain. Quiescent NSCs mainly rely on glycolysis and fatty acid oxidation, whereas the proliferation and terminal differentiation of intermediate progenitors is primarily dependent on mitochondrial OXPHOS (11, 24, 26). Aging is associated with a decline in mitochondrial function, characterised by an accumulation of mtDNA mutations, increased ROS production and impaired mitochondrial respiration, all of which are known to impair adult neurogenesis (34, 35). Multiple studies in mice reveal how a disruption of mitochondrial ETC and OXPHOS function in neural progenitors cause a profound decline in the proliferation and survival of intermediate progenitor cells (IPCs) leading to impaired hippocampal neurogenesis. Examples include the deletion of mitochondrial transcription factor A (TFAM), deletion of subunits of the mitochondrial TCA cycle enzyme alpha-KG-dehydrogenase complex, or deletion of the mitochondrial oxidoreductase protein apoptosis initiating factor (AIF), all of which impairing hippocampal neurogenesis (24, 29, 36). Similarly, disruption of mitochondrial dynamics by deleting the mitochondrial fusion proteins (mitofusin) MFN1 and/or MFN2 impairs NSC self-renewal in the adult hippocampus and cognitive function (11).

The age-associated accumulation of mtDNA mutations may be a main cause of ageing (37, 38). mtDNA mutations are associated with increased mitochondrial ROS which in turn can act as signaling molecules that diminish stem cell self-renewal capacity (39). Proliferating intermediate progenitors normally go through a transient state of oxidative stress to which they respond by rapidly upregulating antioxidant and uncoupling proteins to deal with the increased ROS production (40). An important protein dealing with oxidative stress is the superoxide dismutase enzyme (SOD). Deletion of the extracellular variant of this enzyme (SOD3) causes a decline in adult neurogenesis in the SGZ and impaired cognitive function (41). In addition to impairing NSC self-renewal capacity, increased ROS production also biases NSC differentiation towards the astroglial lineage at the expense of newborn neurons (42, 43). Mice deficient in cytoplasmic SOD (SOD1) and mitochondrial SOD (SOD2) show a decreased adult hippocampal neurogenesis in favour of a overproduction of astrocytes (44). In sum, these studies show that malfunctioning mitochondria in NSCs can impair self-renewal, proliferation and differentiation, which negatively affects adult neurogenesis.

Neurogenesis and Neurodegeneration

The cognitive impairment observed in neurodegenerative diseases, such as Parkinson disease (PD) and Alzheimer disease (AD) has been correlated with a decline in adult neurogenesis (45, 46). These disorders share several key similarities: the progressively develop with age, and are characterised by toxic protein aggregates that target the mitochondria- alpha-synuclein in PD and amyloid-beta (Ab) in AD. Mitochondrial function is critical for mature neurons, where it provides for ATP production, Ca2+ buffering capacity, and regulation of apoptosis (47-49). Similarly, NSCs in the adult brain depend on functional mitochondria for proper cell fate decisions, maturation and survival of newborn neurons (24, 29).

Parkinson disease (PD) is characterised by a loss of dopaminergic neurons in the substantia nigra and the accumulation of Lewy body inclusions consisting of aggregated alpha-synuclein (50). Animal studies describe an impaired neurogenesis in the SGZ and SVZ as a cause for the cognitive decline and depression which often manifest years before the characteristic motor symptoms (51). Such studies also point towards the mitochondria as a key therapeutic target in the affected PD brain. alpha-synuclein was shown to localise to the mitochondrial membrane, impair ETC function and directly cause mitochondrial fragmentation (52, 53). The Pten-induced putative kinase (Pink) and the E3 ubiquitin ligase Parkin are essential for mitochondrial autophagy which provides for a recycling of damaged mitochondria. Loss-of-function mutations in these to proteins cause autosomal recessive variants of PD (54, 55).

Alzheimer disease (AD) is characterised by the progressive accumulation of amyloid plaques and neurofibrillary tangles that cause neurodegeneration and dementia (56). As in the case of PD, impaired hippocampal neurogenesis in the AD brain becomes apparent before the onset of plaques and tangles and has been proposed to contribute to the cognitive impairments that develop with age (46, 57). Recent evidence implicates mitochondrial disfunction as a main cause of impaired neurogenesis in the AD brain and consequently as a potential therapeutic target (58). Improving mitochondrial biogenesis and oxidative function by expression of the transcription regulator Neurod1 improves the maturation and survival of newborn neurones in a mouse model of AD (59). Improving mitochondrial dynamics by activation of the Wnt pathway supports NSC proliferation and differentiation leading to better cognitive function (60). Improving mitochondrial biogenesis and dynamics by activation of cAmp and Creb pathways also promotes hippocampal neurogenesis and cognitive function in transgenic AD mice (61). Taken together, these findings collectively identify mitochondria as a main therapeutic target for improving adult neurogenesis in AD and thereby restore cognitive function.

Targeting Mitochondria in NSCs

Epidemiological data reveal that one third of dementias could be prevented with lifestyle interventions (62). Factors including diet, exercise and cognitive stimulation improve our cognitive reserve and promote brain function in aging and neurodegenerative diseases. They also directly influence adult neurogenesis (63). Improving mitochondrial function has emerged as a promising therapy for restoring adult neurogenesis and promoting cognitive resilience. Two primary therapeutic strategies stand out: targeting endogenous NSCs to stimulate adult neurogenesis directly in the brains of patients, or transplantation of exogenous NSCs to restore lost tissue, improve neurogenic niches and provide trophic support.

Endogenous NSC Therapies

Multiple prominent factors, including a high-fat diet and type 2 diabetes (T2D) not only increase the risk of dementia but also impair adult neurogenesis. T2D impairs the proliferation and differentiation of newborn neurons in the adult brain and it is an established risk factor for cognitive decline associated with AD (64). A high-fat diet impairs adult hippocampal neurogenesis in male rats, likely by interfering with brain development (65). By contrast, a healthy diet and lifestyle have been shown to support adult neurogenesis and improve cognitive function. Under conditions of caloric restriction, adult neurogenesis is stimulated, likely due to increased expression of neurotrophins BDNF (brain derived neurotrophic factor) and NT3 (66). Three other main factors positively regulating cognitive function are: aerobic exercise, environmental enrichment, and dietary supplements. Aerobic exercise stimulates proliferation and maturation of NSCs in the adult brain, by stimulating production of neurotrophins insulin-like growth factor (IGF), vascular endothelial growth factor (VEGF) and BDNF (67). Environmental enrichment works synergistically with aerobic exercise and stimulates maturation and survival of newborn neurons through BDNF signaling (68). A third main factor known to promote adult neurogenesis and improve memory are supplementation regimes, including NAD+, metformin, and dietary antioxidants (69).

NAD+ is an important electron carrier and it used to generate reducing equivalents to fuel mitochondrial OXPHOS. It is also an important coenzyme for sirtuin deacetylases that regulate metabolic homeostasis (70). NAD+ levels decline naturally with age, but NAD+ repletion (eg with NR, nicotinamide riboside) restores mitochondrial function, promotes NSC proliferation and rescues neurogenesis in the ageing SVZ and SGZ (16).

The biguanide compound metformin is an approved drug for treatment of T2D by reducing liver glucose production. It achieves its effect through direct inhibition of mitochondrial ETC complex I and activation of AMPK to confer insulin sensitivity (71). Although metformin inhibits mitochondrial respiration, it has a beneficial effect on mitochondria by improving biogenesis (increases expression of peroxisome proliferator activated receptor gamma co-activator 1 alpha, PGC1a), reducing ROS production from complex I, and preventing apoptosis by inhibiting the mitochondrial membrane permeability transition pore (72-74). Furthermore, metformin was found to promote neurogenesis and enhance memory in animal models through activation of the p53 family member TA73 transcription regulator and activation of the AMPK-aPKC (atypical protein kinase C)-CBP (CREBBP) pathway (75, 76).

Increased ROS production, a common consequence of dysfunctional mitochondria, alters NSC fate decisions and impairs adult neurogenesis (77). Dietary supplementation with antioxidants, including polyphenols, polyunsaturated fatty acids and melatonin, may be a good strategy to promote adult neurogenesis and improve memory in ageing and neurodegeneration. A diet enriched in polyphenols and polyunsaturated fatty acids was found to enhance neurogenesis in the SVZ and SGZ in adult mice brains (78). Polyphenols are plant-derived antioxidants found abundantly in fruits, cocoa, coffee, red wine and curcumin (79, 80). Omega-3 polyunsaturated fatty acids are mainly derived from fish and crustaceans and act as potent antioxidants supporting brain development and adult neurogenesis (81). Finally, melatonin binds directly to melatonin receptors on NSCs and promotes proliferation, differentiation and survival of newborn neurons in the adult brain (82). By doing so, melatonin increases adult hippocampal neurogenesis and reverses oxidative stress (83).

Exogenous NSC Therapies

Recent advances in cell replacement therapy and gene editing have made the transplantation of NSCs a viable treatment option in neurodegenerative and neurodevelopmental disorders, by replacing depleted NSCs in neurogenic niches and providing trophic support for endogenous cells (84). The exogenous NSCs used for transplantation could be obtained in one of four ways: isolation of NSCs from embryonic or adult CNS tissue, differentiation from induced pluripotent stem cells (iPSCs), transdifferentiation to induced NSCs (iNSCs) from patient somatic cells and generation of NSC-like cells from mesenchymal stem cells (MSCs). Direct transplantation of NSCs proved to be a viable treatment option in neurodegenerative disorders, including AD, PD, amyotrophic lateral sclerosis and stroke (85). However, embryonic NSCs are associated with strict ethical boundaries for use in the laboratory and in the clinic, whereas adult NSCs carry the risk of immune rejection following transplantation and are difficult to isolate and expand in culture (86).

As induced NSCs (iNSCs) are reprogrammed from the patient’s own somatic cells, they offer the key advantage of preventing immune rejection, and they are readily maintained and expandable in culture. Somatic cells can be reprogrammed into NSCs either through an intermediate pluripotent state via iPSCs, or by direct lineage conversion to iNSCs (87). Reprogramming of somatic cells is also strongly influenced by mitochondrial metabolism, structure and dynamics. Reprogramming of a somatic cell into a pluripotent iPSC is dependent on a metabolic switch from OXPHOS to glycolysis (88). Promoting glycolysis improves reprogramming efficiency, whereas inhibiting glycolysis reduces reprogramming efficiency (12, 89-91). Upon neuronal differentiation, the cellular metabolism will shift back to OXPHOS, supported by an increased mitochondrial biogenesis, oxygen consumption and ROS production (92). Changing mitochondrial dynamics also influences reprogramming efficiency. Promoting mitochondrial fusion reduces efficiency whereas stimulating mitochondrial fission increases efficiency (93, 94). Another important factor influencing reprogramming efficiency, self-renewal and lineage commitment is mtDNA mutations, which may not be readily apparent in the parent cells but can impair mitochondrial respiration. In particular, such mutations may affect iPSCs derived from patients with mitochondrial diseases or from aged patients (39, 95, 96). Thus, iPSC genotype and metabolic profiling will be an important consideration for their medical use in transplantation therapies. Recent developments of CRISPR-Cas9-based genome editing tools now offer the possibility of correcting or removing disease-causing mutations in iPSCs, such that healthy NSCs or differentiated tissue can be transplanted back into the host (97).

Concluding Remarks

Healthy cognitive processes critically depend on adult neurogenesis. Mitochondria have emerged as key regulators of NSC maintenance and fate decisions during development and in the adult brain. Mitochondrial dysfunction is an important causative factor shared by multiple neurodevelopmental disorders and neurodegenerative conditions. In contrast, interventions aimed at improving mitochondrial health and cellular metabolism enhance neurogenesis and cognitive function, particularly within the process of memory and learning. Mitochondria are therefore an attractive target for correcting NSC dysfunction and restoring neurological processes in cognitive disorders.

Author: Sebastian Florescu, PhD

HOMEPAGE

Published online in December 2019

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