Danping Liu
Pei Guo
Yi Wang
Weihong Li- Basic Medical College, Chengdu University of Traditional Chinese Medicine, Chengdu, China
Neurogenesis has emerged as a promising therapeutic approach for central nervous system disorders. The role of neuronal mitochondria in neurogenesis is well-studied, however, recent evidence underscores the critical role of astrocytic mitochondrial function in regulating neurogenesis and the underlying mechanisms remain incompletely understood. This review highlights the regulatory effects of astrocyte mitochondria on neurogenesis, focusing on metabolic support, calcium homeostasis, and the secretion of neurotrophic factors. The effect of astrocytic mitochondrial dysfunction in the pathophysiology and treatment strategies of Alzheimer’s disease and depression is discussed. Greater attention is needed to investigate the mitochondrial autophagy, dynamics, biogenesis, and energy metabolism in neurogenesis. Targeting astrocyte mitochondria presents a potential therapeutic strategy for enhancing neural regeneration.
1 Introduction
Early childhood experiences, particularly sensory stimulation, are critical for brain development and are intricately linked to neurogenesis, the ongoing generation of new neurons throughout life (Nardou et al., 2019). Neurogenesis, an energy-intensive process, relies heavily on mitochondrial function for adequate adenosine triphosphate (ATP) provision. Consequently, alterations in mitochondrial function can directly impact the efficiency and fidelity of neurogenesis (Khacho et al., 2017).
The brain is primarily composed of neurons and glial cells (Kuramoto et al., 2022). Notably, neuronal and glial mitochondria differentially contribute to neurogenesis. Neuronal mitochondria predominantly provide direct energy supply (Xu et al., 2023), regulate synaptic plasticity (Kochan et al., 2024), etc. Conversely, glial mitochondria primarily offer metabolic support (Allen and Barres, 2009), facilitate myelin sheath protection and repair (Bradl and Lassmann, 2010), and participate in immunomodulation (Morrison et al., 2023). While the impact of neuronal mitochondria on neurogenesis has been extensively investigated (Iwata et al., 2020; Dario et al., 2021; Ozgen et al., 2022), the contribution of glial cell mitochondria, particularly those within astrocytes (the most abundant glial cell type in the brain), remains relatively underexplored.
Neurogenesis exhibits distinct characteristics across different developmental stages, varying in rate, location, function, and the involvement of astrocytic mitochondria. During fetal development, rapid and widespread neurogenesis establishes the fundamental brain architecture. Under physiological conditions, astrocytic mitochondria provide metabolic support and energy, regulating neuronal migration and circuit formation. Mitochondrial dysfunction during this period (e.g., due to maternal infection) can lead to neurodevelopmental abnormalities (Kostović et al., 2019; Vasistha et al., 2020). In infancy and early childhood, neurogenesis slows and becomes localized to specific brain regions, supporting circuit refinement and functional maturation. Astrocytic mitochondria contribute to synaptogenesis and myelination, maintaining neuronal homeostasis. Dysfunction at this stage (e.g., due to brain injury) can disrupt circuit development (Bosworth and Allen, 2017; Ortiz-González, 2021). In adulthood, neurogenesis is primarily associated with learning, memory, and mood regulation. Astrocytic mitochondria support the maintenance of neural stem cell niches and synaptic plasticity. Dysfunction in adulthood (e.g., from chronic stress) can contribute to cognitive decline and neurological disease (Du et al., 2018; Morita et al., 2019).
Given the critical role of astrocytic mitochondria in neurogenesis and the significant research implications, this review focuses on their contribution to adult neurogenesis. We explore how astrocytic mitochondrial dysfunction impacts adult neurogenesis and its connection to neurological disorders, aiming to provide novel insights and therapeutic strategies for these conditions.
Despite evidence supporting adult neurogenesis in mammals since the 1960s (Altman, 1962; Altman and Das, 1965; Kaplan and Hinds, 1977), its frequency (Sorrells et al., 2018) and functional significance (Kempermann, 2012) remain debated. Neurogenesis, the process by which neural stem cells (NSCs) differentiate into mature neurons (Gage, 2019), encompasses NSC proliferation and differentiation, neuronal precursor cell migration and differentiation, and ultimately, the integration of newborn neurons into existing neural circuits (Ming and Song, 2011). In the adult mammalian brain, two primary neurogenic niches harboring endogenous NSCs are the subventricular zone (SVZ) lining the lateral ventricles (Alvarez-Buylla and Garcia-Verdugo, 2002) and the subgranular zone (SGZ) of the hippocampal dentate gyrus (Gage, 2000). Recent research has also highlighted the potential for neurogenesis in the neocortex (Zamboni et al., 2020). Neurogenesis plays a critical role in brain development and sculpting (Semple et al., 2013) and the formation of neural circuits (Obernier and Alvarez-Buylla, 2019) during early life. In the adult brain, endogenous neurogenesis contributes significantly to neuroplasticity (Moreno-Jiménez et al., 2019) and neural repair following injury (Jessberger and Gage, 2014; Denoth-Lippuner and Jessberger, 2021). Notably, the cellular constituents of the neurogenic niche microenvironment, including glial cells (Kyle et al., 2019), exert a significant influence on adult neurogenesis.
Astrocytes, derived from the neuroectoderm (Kang et al., 2013), differentiate from radial glial cells early in development (Santos et al., 2017) and neural progenitor cells at later stages (Nagao et al., 2016). Comprising a significant portion of the central nervous system (CNS) (Hasel and Liddelow, 2021), astrocytes provide essential metabolic support to neurons (Hélène et al., 2023), contribute to calcium homeostasis (Jones et al., 2018), and supply neurotrophic factors (Zhang et al., 2020). Astrocyte dysfunction has profound implications for CNS health and function (Yang et al., 2022).
Mitochondria, double-membrane-bound organelles (Suomalainen and Nunnari, 2024), are primarily known for generating ATP through oxidative phosphorylation, placing them at the core of nutrient sensing and metabolic regulation. Beyond energy production, mitochondria participate in diverse cellular processes, including metabolism, metabolite and ion transport, apoptosis regulation, inflammation, signal transduction, and mitochondrial DNA inheritance (Szabo and Szewczyk, 2023). Mitochondrial function is inextricably linked to cellular function and profoundly influences overall cellular health. Activated astrocytes are a common feature in various neurodegenerative diseases and CNS injuries. Astrocytic mitochondrial function is crucial for maintaining overall brain metabolism, synaptic transmission, and neuroprotection. Impaired astrocytic mitochondrial function can lead to energy deficits, calcium dysregulation, inflammation, and glutamate imbalance (Gollihue and Norris, 2020). Furthermore, studies have revealed age-related changes in the distribution of astrocytic mitochondria within the neurogenic SVZ. In young mice, astrocytic mitochondria are perinuclear, exhibiting a dense matrix rich in cristae. In contrast, aged mice display a more dispersed cytoplasmic distribution of mitochondria in astrocytes, characterized by a lighter matrix, fewer cristae, and dilated cristae morphology (Capilla-Gonzalez et al., 2014). The findings underscore the dynamic nature of astrocytic mitochondria and their potential vulnerability to age-related decline and dysfunction.
The role of astrocytic mitochondria in neurogenesis remains relatively underexplored. A comprehensive understanding of this role is crucial for elucidating the pathophysiological mechanisms underlying neurological disorders, particularly those characterized by impaired neuronal function. The following section will examine the relationship between neurogenesis and central nervous system disorders, focusing on Alzheimer’s disease and depression as illustrative examples.
2 Central nervous system diseases and adult neurogenesis
Alzheimer’s disease (AD) and major depressive disorder (MDD), two prevalent central nervous system disorders, are strongly associated with impaired neurogenesis. Astrocytic mitochondrial dysfunction can modulate neurogenesis, thereby influencing disease progression. This section focuses on these two disorders to elucidate the relationship between astrocytic mitochondrial dysfunction and the pathophysiology of AD and MDD, as illustrated in Figure 1.
Figure 1. Impact of astrocytic mitochondrial dysfunction and impaired neurogenesis on neurological disorders. (a) Targeting astrocytic mitochondria and neurogenesis in depression. In depression, several signaling pathways within astrocytic mitochondria are impaired, including TCA signaling and glutamate uptake. Astrocytic mitochondrial dysfunction leads to decreased NSC proliferation and differentiation, reduced ATP and BDNF levels, increased ROS and Glu, and neuronal damage. (b) Targeting astrocytic mitochondria and neurogenesis in AD. In AD, astrocytic mitochondrial dysfunction affects pathways such as TCA cycle signaling and FAO. This dysfunction results in decreased NSC proliferation and differentiation, reduced ATP production, increased ROS, and accumulation of Aβ. NSC, neural stem cell; ROS, reactive oxygen species; Glu, glutamate; BDNF, brain-derived neurotrophic factor; TCA, tricarboxylic acid cycle; Aβ, amyloid-β plaques; AD, Alzheimer’s disease; FAO, fatty acid oxidation; ATP, adenosine triphosphate.
2.1 Alzheimer’s disease
AD, the most prevalent neurodegenerative disorder, is characterized by progressive cognitive decline and currently lacks effective treatment. While amyloid-β (Aβ) and tau protein accumulation are central to AD pathogenesis (Sardar Sinha et al., 2018; Liang et al., 2021). A significant decline in neurogenesis is also a hallmark of AD pathophysiology, observed in both patients and animal models (Polis et al., 2020). This decline in neurogenesis, crucial for learning and memory, contributes significantly to the cognitive impairments seen in AD.
In AD, astrocytes, key players in supporting neurogenesis, exhibit a rapid response to injury, undergoing significant molecular, cellular, and morphological changes (Cassé et al., 2018). These alterations disrupt astrocytic support for neural stem cells and newborn neurons, impairing stem cell proliferation and progenitor migration.
Furthermore, astrocytic mitochondrial dysfunction, exacerbated by risk factors like the APOE4 genotype (Lin et al., 2019; Schmukler et al., 2020; Fortea et al., 2024), contributes directly to AD progression through oxidative stress, impaired fatty acid oxidation (FAO), glutamate accumulation, and energy deficits (Preman et al., 2021). This mitochondrial dysfunction further impairs neurogenesis, reduces neuronal plasticity, and exacerbates neuronal vulnerability to Aβ and tau pathologies, accelerating disease progression and ultimately contributing to the debilitating dementia characteristic of AD.
2.2 Major depressive disorder
MDD is a severe, chronic psychiatric illness with increasing prevalence and mortality, posing a substantial societal burden (Choi et al., 2019). Reduced neurogenesis in the dentate gyrus is considered a key factor in MDD pathogenesis (Jacobs et al., 2000). Astrocytes are crucial for maintaining neurogenesis, yet in preclinical models of depression, such as chronic mild stress (CMS), astrocytes exhibit mitochondrial dysfunction and reduced numbers (Shu et al., 2019). Moreover, compromising astrocytic function, for instance through lipopolysaccharide (LPS) exposure, induces mitochondrial damage and impairs neuronal synaptic plasticity (Li et al., 2023). Both mitochondrial uncoupling protein 2 (UCP2) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) are linked to astrocytic mitochondrial function and implicated in MDD pathogenesis; UCP2 knockout mice display exacerbated depressive-like behaviors and impaired neurogenesis under CMS induction (Du et al., 2016). While PGC-1α deficiency in astrocytes disrupts astrocyte morphogenesis and neuronal synapse development (Zehnder et al., 2021).
This astrocytic mitochondrial dysfunction significantly contributes to the core clinical symptoms of MDD. The resulting reduction in neurogenesis, particularly within the hippocampus, contributes to depressed mood, anhedonia, and cognitive deficits. Furthermore, mitochondrial dysfunction leads to decreased ATP production and can contribute to extracellular glutamate (Glu) accumulation, both of which can exacerbate neuronal damage and dysfunction. Impaired astrocytic support, coupled with increased inflammation and oxidative stress, likely hinders the brain’s capacity to adapt to stress and form new positive associations, perpetuating the depressive state. The loss of astrocytic metabolic support further compromises neuronal function and resilience, exacerbating stress responses and potentially leading to anhedonia and lack of motivation. Moreover, disrupted neurotrophic factor signaling associated with astrocyte dysfunction can contribute to atrophy in brain regions associated with mood regulation, further compounding the severity of symptoms.
Given the crucial role of neurogenesis in both depression and Alzheimer’s disease, a deeper understanding of the mechanisms by which astrocytic mitochondria regulate this process is essential for elucidating the pathophysiology of these disorders and developing novel therapeutic strategies.
3 Role of astrocytic mitochondria in adult neurogenesis
To further explore how astrocytic mitochondria influence neurogenesis, we will delve into the specific mechanisms underlying their role in adult neurogenesis.
As depicted in Figure 2, astrocytic mitochondria influence neurogenesis through a variety of metabolic pathways, including oxidative phosphorylation, fatty acid oxidation, amino acid metabolism, and maintenance of calcium homeostasis. Furthermore, astrocytes support neurogenesis by secreting neurotrophic factors. The metabolic and regulatory functions act in concert to ensure proper neurogenic progression and contribute significantly to overall nervous system homeostasis.
Figure 2. Influence of astrocytic mitochondria on neurogenesis. (1a) Functional astrocytic mitochondria through OXPHOS provide energy and appropriate levels of ROS for neurogenesis. (1b) Dysfunctional astrocytic mitochondria exhibit reduced OXPHOS, leading to decreased ATP production and increased ROS, impacting NSC proliferation and differentiation. (2a) FAO pathway in astrocytic mitochondria provides energy and synthesizes lipid substrates to support neuronal synapse formation, cell membrane synthesis, and myelination. (2b) Astrocytic mitochondrial dysfunction disrupts FAO, reducing ATP production and interfering with lipid homeostasis, inhibiting the synthesis of lipids required for neuronal synapses, cell membranes, and myelin. (3a) Functional astrocytic mitochondria provide energy for glutamine-glutamate homeostasis and GSH synthesis in astrocytes, supporting the development and maintenance of neural circuits. (3b) Astrocytic mitochondrial dysfunction disrupts glutamine-glutamate homeostasis and GSH synthesis, leading to neuronal excitotoxicity, decreased ATP, and increased ROS. (4a) Astrocytic mitochondria-dependent calcium dynamics regulate synaptic transmission and plasticity, modulate energy production, and directly influence the development and maintenance of neural circuits. (4b) Alterations in astrocytic calcium levels result in reduced energy production, increased ROS, and impaired synaptic plasticity. (5a) Functional astrocytic mitochondria promote the release of neurotrophic factors from astrocytes, thereby facilitating neurogenesis. (5b) Astrocytic mitochondrial dysfunction leads to decreased neurotrophic factor release, negatively impacting neurogenesis. OXPHOS, oxidative phosphorylation; ATP, adenosine triphosphate; ROS, reactive oxygen species; ATP, adenosine triphosphate; NSC, neural stem cell; NPC, neural progenitor cell; TCA, tricarboxylic acid cycle; ER, endoplasmic reticulum; Golgi, Golgi apparatus; FAO, fatty acid oxidation; FA, fatty acid; Glu, glutamate; Gln, glutamine; GSH, glutathione; αKG, α-ketoglutarate; Ca 2+, calcium ion; BDNF, brain-derived neurotrophic factor; NGF, nerve growth factor; FGF-2, fibroblast growth factor 2; CNTF, ciliary neurotrophic factor; VEGF, vascular endothelial growth factor; FGFR1, fibroblast growth factor receptor 1; GDNF, glial cell line-derived neurotrophic factor.
3.1 Metabolic support
Astrocytes utilize diverse metabolic pathways, including glycolysis, the pentose phosphate pathway, and oxidative phosphorylation for glucose metabolism (Zhang et al., 2023). Fatty acid metabolism in astrocytes is characterized by fatty acid oxidation and sphingolipid metabolism, while amino acid metabolism involves neurotransmitter, serine, and kynurenine pathways. This metabolic support provides energy not only for astrocytes themselves but also for neurons, playing a critical role in maintaining neuronal health and facilitating interneuronal signaling. Neurogenesis requires extensive metabolic reprogramming (Maffezzini et al., 2020), including shifts in cellular energy sources. Mitochondria are central to this metabolic plasticity and are increasingly recognized as key regulators of neural stem cell fate and neurodevelopment (Khacho et al., 2019). Astrocytic mitochondria are heavily involved in oxidative phosphorylation, fatty acid oxidation, and amino acid metabolism, processes intimately linked to neurogenesis.
3.1.1 Oxidative phosphorylation
Although astrocytes primarily rely on glycolysis for energy production (Vicente-Gutierrez et al., 2021), they can utilize oxidative phosphorylation within their mitochondria to rapidly generate ATP under conditions of high energy demand, sufficient oxygen supply, low lactate availability, or high lactate requirements. Neuronal differentiation of NSCs necessitates a metabolic shift toward oxidative phosphorylation (Bifari et al., 2020). This shift is not only crucial for meeting increased energy demands but also plays a significant role in regulating brain metabolism and antioxidant defense (Rose et al., 2020; Rubio-Atonal and Ioannou, 2023).
NSC proliferation and differentiation are energy-intensive processes (Cassiano et al., 2022). The metabolic switch in astrocytes from glycolysis to oxidative phosphorylation enhances energy supply, supporting these neurogenic processes (Chen et al., 2023). During oxidative phosphorylation, NADH and FADH2 serve as essential electron sources for the electron transport chain (ETC) (Melin and Hellwig, 2020), donating electrons to Complex I and Complex II, respectively, to drive ATP synthesis (Vasan et al., 2022). This process also generates ROS as a byproduct (Parousis et al., 2018). While excessive ROS can be detrimental to neuronal health (Sies et al., 2024), moderate ROS levels can induce neurogenesis (D’Angelo et al., 2018; Aravind et al., 2021).
ROS are proposed to play a key role in regulating stem cell homeostasis (Chen et al., 2021; Maraldi et al., 2021), influencing the reversible equilibrium between NSC quiescence and activation (Hwang et al., 2021). ROS modulate NSC fate through various signaling pathways. ROS activate the Nrf2-ARE pathway (Kahroba et al., 2021), promoting nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2). Nrf2 subsequently binds to the antioxidant response element (ARE), enhancing expression of antioxidant genes like heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO1) (Sun et al., 2021), thus protecting NSCs from oxidative damage. ROS also activate the PI3K/Akt pathway by phosphorylating and activating cell membrane growth factor receptors. Activated PI3K converts phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-trisphosphate (PIP3), recruiting and activating Akt (Le Belle et al., 2011; Hansen et al., 2019). Akt promotes NSC survival by inhibiting pro-apoptotic proteins (e.g., Bad) and upregulating anti-apoptotic proteins (e.g., Bcl-2) (Tao et al., 2017). Furthermore, ROS activate the MAPK/ERK pathway by stimulating cell surface receptors (e.g., growth factor receptors) or directly modulating intracellular signaling molecules, leading to RAS activation. This triggers a downstream cascade involving RAF kinase, MEK (MAPK/ERK kinase), and ultimately ERK phosphorylation (Zheng et al., 2021). Activated ERK translocates to the nucleus, regulating genes involved in cell proliferation and differentiation, such as Bcl-2 and Cyclin D1, promoting NSC differentiation (Kučera et al., 2016; Wang et al., 2021).
Under pathological conditions, inhibiting oxidative phosphorylation in astrocytes with mitochondrial inhibitors leads to significant ATP depletion (Astakhova et al., 2019), suggesting that reduced astrocytic oxidative phosphorylation can negatively impact NSC proliferation and differentiation by limiting energy availability. Studies have shown that NSCs accumulate ROS during reoxygenation, and inhibiting ROS biosynthesis counteracts their proliferation and neurogenic potential (Hameed et al., 2015). Conversely, excessive ROS can inhibit ETC Complex I activity (Dong et al., 2020) and drive stem cells out of quiescence, ultimately depleting the stem cell pool (Rossi et al., 2008). Furthermore, astrocyte-induced oxidative stress can contribute to neuronal death (Sulimai et al., 2021). These findings collectively demonstrate the multifaceted role of astrocytic oxidative phosphorylation in influencing neurogenesis through both ATP generation and ROS production.
3.1.2 Fatty acid oxidation pathway
Astrocytic mitochondrial fatty acid oxidation (FAO) supports neurogenesis by providing both energy and metabolic intermediates (Lee et al., 2021). FAO involves the breakdown of fatty acids within the mitochondrial matrix into acetyl-CoA, releasing energy and generating substantial amounts of citrate, FADH2, and NADH to fuel oxidative phosphorylation (Mekala et al., 2021; Zhang T. et al., 2022), thereby providing energy for neurons (Lee et al., 2021). Citrate, an intermediate in the tricarboxylic acid (TCA) cycle, contributes to ATP production (Guo et al., 2022) and can also be converted to acetyl-CoA via ATP citrate lyase, influencing neurogenesis. Astrocytic FAO is particularly crucial for the synthesis of lipid membranes, especially those of neuronal cells (Ali and Szabó, 2023). Adult neural stem cells in the brain rely on FAO to support both aerobic respiration and proliferative activity (Stoll et al., 2015).
Acetyl-CoA is converted to malonyl-CoA, which is subsequently processed through the endoplasmic reticulum and Golgi apparatus to form palmitate, a key substrate for lipid synthesis (Wegner et al., 2021). Acetyl-CoA can induce neural stem cell exit from quiescence, enhance proliferation and differentiation (Zhou et al., 2019), and contribute to phospholipid synthesis, influencing neuronal synaptic strength, axonal growth, and cell membrane and myelin formation (Fadó et al., 2021; Roy and Tedeschi, 2021).
Studies have demonstrated that the brain heavily relies on astrocytic mitochondrial oxidative phosphorylation for fatty acid degradation and maintenance of lipid homeostasis. Astrocytic mitochondrial dysfunction can activate microglia and inhibit the biosynthesis of fatty acids and phospholipids required for myelin replenishment, gradually inducing neuroinflammation and neurodegeneration (Mi et al., 2023), thereby negatively impacting neurogenesis. Another study showed that knocking out carnitine palmitoyltransferase 1A (CPT1A), a key enzyme in mitochondrial FAO, in adult mouse astrocytes affects physiological ROS production (Morant-Ferrando et al., 2023), which can also influence neurogenesis. In vitro experiments have demonstrated that exposing quiescent adult neural stem cells to malonyl-CoA dose-dependently prevents quiescence induction and even promotes proliferation, indicating the importance of malonyl-CoA levels in regulating neural stem cell proliferation (Knobloch et al., 2017). These findings collectively highlight the influence of astrocytic mitochondrial FAO on neurogenesis through energy provision and the generation of key metabolic intermediates.
3.1.3 Amino acid metabolic pathways
Astrocytic mitochondrial amino acid metabolism significantly influences neurogenesis (Guo et al., 2023), particularly through the synthesis and recycling of the neurotransmitter glutamate and the synthesis of antioxidants such as glutathione. A key astrocytic function is the rapid removal of neurotransmitters from the synaptic cleft (Dewa et al., 2024). In the glutamate-glutamine cycle, neurons and astrocytes cooperate closely through neurotransmitter recycling (Andersen et al., 2022). Glutamate-induced excitotoxicity is a recognized cause of neuronal cell death (Zhang Z. et al., 2022), and the uptake and conversion of glutamate is an energy-intensive process heavily reliant on mitochondrial energy supply (Havelund et al., 2019).
Astrocytes take up excess glutamate from the synaptic cleft via transporters to prevent excitotoxic neuronal damage (Qu et al., 2021). Within astrocytes, glutamate is converted to glutamine in the cytoplasm by glutamine synthetase (Luo et al., 2019). Alternatively, glutamate can be converted to α-ketoglutarate (αKG) within mitochondria through reactions catalyzed by glutamate dehydrogenase or aminotransferases (Pecchillo Cimmino et al., 2022). αKG, a key intermediate in the TCA cycle, plays a crucial role in cellular energy metabolism (Iwaniak et al., 2022). Glutamate is also a precursor for glutathione synthesis. In the cytoplasm, glutamate and cysteine are combined by cysteine ligase to form γ-glutamylcysteine. This dipeptide then reacts with glycine, in an ATP-dependent reaction catalyzed by glutathione synthetase, to form glutathione. Glutathione is a potent antioxidant crucial for maintaining mitochondrial integrity and function, scavenging free radicals and protecting mitochondria from oxidative damage. Astrocytic mitochondria, by providing energy, support glutamate uptake, conversion, and glutathione synthesis. This is essential for maintaining homeostasis in the glutamate-glutamine cycle and regulating the microenvironment necessary for neurogenesis. A balanced glutamate-glutamine cycle helps prevent excitotoxicity, while glutathione, through its antioxidant properties, mitigates oxidative stress-induced damage to neural cells, protecting neuronal function and neurogenesis.
Glutamate exhibits a biphasic dose–response on neurogenesis: low doses are beneficial, while excessive glutamate levels, due to increased release or decreased removal, can lead to neuronal atrophy and depression (Rubio-Casillas and Fernández-Guasti, 2016). Furthermore, modulating glutamate receptor subtypes can regulate NSC proliferation and differentiation. For instance, regulating metabotropic glutamate receptor subtype 4 (mGluR4) can influence NSC proliferation and apoptosis by inhibiting Cyclin D1 expression, promoting pro-caspase-8/9/3 activation, disrupting the balance between Bcl-2 and Bax (Bcl-2-associated X protein), and downregulating the expression of Gli-1, a transcription factor in the sonic hedgehog signaling pathway (Reichenbach et al., 2018; Zhang et al., 2018). Modulating metabotropic glutamate receptor subtype 5 (mGluR5) can influence neurogenesis by affecting the expression of the glutamate transporter SLC1A3 (also known as EAAT1/GLAST), thereby regulating stem cell activation and proliferation in different microenvironments. Astrocyte-derived mitochondrial ROS influence glucose utilization via glutathione metabolism, thereby modulating redox status and potentially neuronal survival (Vicente-Gutierrez et al., 2019). Glutathione depletion can exacerbate oxidative stress (Jaganjac et al., 2022), lead to mitochondrial dysfunction (Quinzii and Lopez, 2021), impair neural stem cell proliferation (Jeong et al., 2018) and differentiation (Aoyama, 2021), and increase apoptosis (Wang L. et al., 2020). In pathological conditions, astrocytic mitochondrial dysfunction disrupts glutamate metabolism and glutathione synthesis, contributing to neuronal damage and impaired neurogenesis through excitotoxicity and oxidative stress.
3.2 Calcium homeostasis
A key function of astrocytic mitochondria is buffering cytosolic calcium and regulating intracellular calcium homeostasis (Ahn et al., 2022; Lee et al., 2022), essential for cellular functions involved in neurogenesis. Calcium signaling networks profoundly influence neural stem cell proliferation, migration, and differentiation (Toth et al., 2016). Through mitochondrial regulation of calcium signaling, astrocytes exert multi-faceted control over neurogenesis (Glaser et al., 2019).
Firstly, astrocytes, via mitochondrial calcium signaling, influence energy metabolism and modulate synaptic activity. For example, mitochondrial calcium status regulates astrocytic glutamate uptake and vesicular release, impacting neuronal energy supply and synaptic transmission strength (Hirrlinger and Nimmerjahn, 2022; Satarker et al., 2022). Mitochondrial calcium also modulates the activity of TCA cycle enzymes, influencing ATP production (Assis et al., 2022). Furthermore, the action of mitochondrial proteins determines mitochondrial localization within astrocytes, impacting calcium wave propagation, mitochondrial energy production, and the regulation of neuronal function (Stephen et al., 2015). Critically, mitochondria-dependent calcium dynamics in astrocytes regulate synaptic transmission and plasticity (Serrat et al., 2021), directly influencing the development and maintenance of neural circuits. This mitochondria-based calcium signaling ensures adequate energy supply for astrocytes and provides essential metabolic support and signaling cues to neural stem cells, ultimately impacting neurogenesis.
Recent studies have shown that autoimmune inflammation can disrupt astrocytic calcium signaling, leading to increased glutamatergic gliotransmission and impaired astrocyte-mediated synaptic plasticity (Baraibar et al., 2024). This calcium dysregulation disrupts neuron-astrocyte communication and weakens synaptic stability and function, negatively impacting neuronal health. Mitochondria, by regulating intracellular calcium levels, play a critical role in maintaining cell survival, indirectly influencing neurogenesis (Klocke et al., 2023). Excessive calcium accumulation can trigger opening of the mitochondrial permeability transition pore (mPTP), leading to astrocyte death (Sun et al., 2018; Bauer and Murphy, 2020). This cell death compromises astrocytic support for surrounding neurons, impairing neuronal health and disrupting neurogenesis. Mitochondria-regulated calcium signaling can also activate specific signaling pathways, such as NF-κB or CREB, which regulate gene expression related to neurogenesis, directly impacting neural stem cell proliferation and differentiation. Through the modulation of these transcription factors, calcium signaling plays a significant role in the pathological regulation of neurogenesis (Huang et al., 2022).
In summary, by maintaining calcium homeostasis, astrocytic mitochondria exert profound effects on synaptic activity, synaptic plasticity, and cell survival, particularly under pathological conditions, thereby influencing the progression of neurogenesis.
3.3 Neurotrophic factor secretion
Astrocytic mitochondria influence the production and release of various neurotrophic factors (Ren et al., 2020; Zhao et al., 2021), which play a critical role in neurogenesis (Preez et al., 2021). Studies have demonstrated that neurotrophic factors secreted by astrocytes, such as brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and fibroblast growth factor 2 (FGF2), promote neuroblast migration, neural stem cell proliferation, survival, and differentiation (Brown et al., 2021; Lin et al., 2021; Wu et al., 2023). Astrocyte-derived ciliary neurotrophic factor (CNTF) enhances neurogenesis by promoting NSC proliferation and differentiation via the FAK-JNK pathway and by modulating the expression of related cytokines such as leukemia inhibitory factor (LIF) and interleukin-6 (IL-6) (Jia et al., 2018). Vascular endothelial growth factor (VEGF) also stimulates neurogenesis by binding to its receptor and activating multiple signaling pathways, including PI3K/Akt and MAPK (Preez et al., 2021; van den Berg et al., 2021).
Under pathological conditions, downregulation of astrocytic FGF2 and its receptor, FGFR1, impairs glutamatergic synapse formation and ultimately reduces neurogenesis (Choi et al., 2022). Studies of astrocytes under recurrent hypoglycemic conditions, both in vivo and in vitro, have revealed mitochondrial dysfunction and decreased secretion of BDNF and glial cell line-derived neurotrophic factor (GDNF). Protecting mitochondrial function restores astrocyte viability and neurotrophic factor production and secretion (Gao et al., 2021). These findings collectively demonstrate that astrocytic mitochondria influence various stages of neurogenesis through the modulation of neurotrophic factor production and release.
4 Therapeutic strategy for neurological disorders
The previous chapter detailed the mechanisms by which astrocytic mitochondria influence adult neurogenesis. Building upon these findings, this chapter will explore potential therapeutic strategies targeting astrocytic mitochondria to promote neurogenesis and ameliorate neurological disease symptoms, focusing on Alzheimer’s disease and depression as illustrative examples.
Targeting astrocytic dysfunction, particularly mitochondrial impairment, represents a promising therapeutic strategy for AD (Galea et al., 2022). Restoring astrocytic energy metabolism has demonstrated the potential to partially reverse AD pathology and ameliorate clinical symptoms (Mamelak, 2017). Specifically, addressing APOE4-induced mitochondrial dysfunction and autophagy deficits offers compelling targets for pharmacological intervention. For example in vitro studies reveal that APOE4-expressing astrocytes negatively impact dendritic spine dynamics in neuron-astrocyte co-cultures (Lee et al., 2023), suggesting that early intervention targeting APOE4-mediated mitochondrial dysfunction may be crucial for delaying AD progression. These findings underscore the profound impact of astrocytic mitochondrial dysfunction on AD pathophysiology and highlight the therapeutic potential of targeting these mechanisms.
In the context of depression, therapeutic strategies targeting astrocytic mitochondria and neurogenesis are emerging. Mitochondrial transplantation has shown promise in preclinical models, ameliorating LPS-induced depressive-like behavior by reducing neuroinflammation and increasing BDNF expression and neurogenesis (Wang et al., 2019). Modulating astrocytic sigma-1 receptor (Sig-1R) activity promotes mitochondrial transfer from astrocytes to neurons, enhancing neuronal survival and exerting antidepressant-like effects (Wang Y. et al., 2020). Furthermore, targeting the RARγ-GLT-1 pathway in astrocytes within retinoic acid-induced depression models promotes neurogenesis and mitigates depressive-like behavior (Huang et al., 2024). These findings emphasize the therapeutic potential of targeting astrocytic mitochondria to enhance neurogenesis and alleviate depressive symptoms.
5 Summary
Endogenous neurogenesis, with its inherent self-repair capabilities, potential for long-term therapeutic effects, and relatively low risk of side effects, represents a promising therapeutic strategy for neurological disorders. Enhancing endogenous neurogenesis has become a focal point of current research, with mitochondria playing a crucial role in this process. Current drug development efforts predominantly focus on directly modulating neuronal function, often overlooking the contribution of astrocytes. Future research should prioritize investigating the reactive changes in astrocytes during disease progression and their direct impact on neurogenesis. Specifically, exploring astrocytic mitophagy, mitochondrial dynamics, biogenesis, and energy metabolism will likely reveal detailed mechanisms underlying their influence on neurogenesis. This knowledge promises to uncover novel therapeutic avenues for neurological disorders, deepen our understanding of neural stem cell regulation, and ultimately lead to the development of more effective treatments.
Author contributions
DL: Conceptualization, Project administration, Resources, Visualization, Writing – original draft, Writing – review & editing. PG: Writing – review & editing. YW: Writing – review & editing. WL: Conceptualization, Funding acquisition, Supervision, Writing – review & editing.
Funding
The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This research was funded by the National Natural Science Foundation of China (81873204) and National Administration of Traditional Chinese Medicine (2024MS006).
Acknowledgments
Figures 1, 2 of the graphical representations were generated by Figdraw (www.figdraw.com).
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The authors declare that no Generative AI was used in the creation of this manuscript.
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Keywords: astrocytes, mitochondrial, neurogenesis, Alzheimer’s disease, major depressive disorder
Citation: Liu D, Guo P, Wang Y and Li W (2024) Regulation of adult neurogenesis: the crucial role of astrocytic mitochondria. Front. Mol. Neurosci. 17:1516119. doi: 10.3389/fnmol.2024.1516119
Edited by:
Muddanna Sakkattu Rao, Kuwait University, KuwaitCopyright © 2024 Liu, Guo, Wang and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Weihong Li, bHdoQGNkdXRjbS5lZHUuY24=