Astrocyte Mitochondria in White-Matter Injury Part 3

Astrocyte Mitochondrial Response to Injury

Stimuli that initiate astrocyte reactivity such as aging, injury, and diseases similarly affect astrocyte mitochondria, leading to dysfunction. 

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The hallmarks of this dysfunction consist of loss of Ca2+ regulation [134, 135], excessive production of ROS, initiation of cell death cascades, and opening of mitochondrial permeability transition pores (mtPTP; [136]). 

Elevated cytosolic Ca2+ increases and Ca2+ transients lead to more frequent Ca2+ oscillations, and excess Ca2+ accumulation in mitochondria depletes mitochondrial membrane potential, leading to impaired ATP production and opening of mtPTP. 

Opening of mtPTP results in cytochrome c release as well as other cytokines and ROS [137]. Considering the astrocytic network and the extent of communication among astrocytes, mitochondrial dysfunction, recruiting more astrocytes, and expanding the area of their network can have far-reaching effects. As a result, for instance, β-amyloid-induced oxidative stress in astrocytes causes extensive neuronal damage away from amyloid deposition areas [138, 139]. 

Neuronal injury can be further potentiated by the release of cytokines, ROS, and inflammatory factors [140–142]. Experiments adding FC to astrocyte cultures, which dissipates astrocyte mitochondrial membrane potentials, reduce glutamate uptake leading to increased neurotoxicity [120]. 

Likewise, targeting the astrocyte electron transport chain caused diffuse neuronal death [128]. These pieces of evidence imply that astrocytic mitochondria are crucial to support neurons and their function. 

Therefore, mitochondrial dysfunction impedes the protective roles of astrocytes, suggesting that targeting astrocyte mitochondria may provide therapeutic approaches to surrounding neurons. Mitochondria at the astrocyte end-feet are associated with cerebrovascular structures and demonstrate high metabolic activity and dynamic Ca2+ signaling [143]. 

However, how astrocyte mitochondrial dynamics contribute to NVU, BBB, and/or cerebrovascular pathologies such as vascular dementia remain underexplored.

Mitochondrial Trafficking Between Astrocytes and Neurons

Astrocyte mitochondria can also be central to the protective and beneficial roles of astrocytes. Responding to the energy demands of astrocytes, mitochondria may regulate the release of growth factors, support synaptic function, and/or form a glial scar. 

Consistent with this, following a brain injury astrocytes cannot initiate a protective proliferative response if their mitochondria are dysfunctional [128]. Indeed, astrocytes dispose of their dysfunctional mitochondria via mitophagy [144], presumably to minimize the deleterious effects. Interestingly, astrocytes can take up or traffic mitochondria to and from other cells. 

For instance, mitochondria from retinal ganglion cells are taken up by astrocytes, while mitochondria from astrocytes can be transferred to neurons, suggesting bidirectional trafficking of mitochondria between astrocytes and neurons. Current evidence suggests that the purpose of this activity is to deliver damaged mitochondria from neurons to astrocytes to undergo mitophagy, while healthy mitochondria moving from astrocytes to neurons support neurons in distress. Mitochondria are released in vesicles in a Ca2+-dependent CD38-cADPR signaling pathway [145]. 

Subsequently, upregulation of CD38 significantly augments the release of mitochondria-containing vesicles under in vitro and in vivo conditions [145]. Mitochondria originating from astrocytes fuse with the neuronal mitochondria located in the penumbra region and enhance the survival of neurons. Expectedly, the downregulation of CD38 in an ischemia model negatively impacted the outcome measures, supporting the observation that astrocyte-mediated mitochondrial release is mediated by CD38 signaling in the brain. 

There is significant interest in whether a similar survival mechanism or lack thereof, contributes to neurodegenerative diseases. Using primary neural cells and human pluripotent stem cell-derived neural cells (hPSCs), a dynamic transfer of mitochondria from astrocytes and neural cells into astrocytes was shown via CD38/cADPR signaling and involving Miro1 and Miro2. Introducing Alexander disease (AxD) -associated hot spot mutations into the GFAP gene of hPSCs impaired mitochondrial transfer between neural cells and astrocytes and revealed that AxD-associated mutations in the GFAP gene disrupted astrocytic mitochondria transfer, providing a potential pathogenic mechanism in AxD [146]. 

Interestingly, Miro1, as well as Miro2, played a role in mitochondrial transfer, which seems plausible considering the involvement of the two GTPases in intracellular mitochondrial transport and trafficking [147, 148]. The potential of Miro1 to regulate mitochondrial transfer from mesenchymal stem cells into airway epithelial cells and cardiomyocytes has been previously shown [149, 150]. 

Interestingly, both Miro1 and Miro2 have two EF-hand Ca2+-binding domains [147, 151]; whether they cross-talk with CD38/cADPR signaling remains to be explored. Determining whether mitochondrial transfer between astrocytes and from neuronal cells into astrocytes also occurs in vivo, and revealing more detailed cellular functions of the transfer, require further investigation.

Astrocyte Mitochondria as a Therapeutic Target for Neuronal Diseases

Therapeutic approaches targeting mitochondria for various brain injuries and neurodegenerative diseases using antioxidants, mtPTP inhibitors, uncouplers, and alternative fuels have been a long-standing interest. 

Conventionally, the majority of these investigations have been performed with the intent of rescuing neuronal mitochondria. However, astrocytic mitochondrial dysfunction may have more widespread effects based on the role, function, and location of astrocytes in various brain structures, causing extensive Ca2+ dysregulation, inflammatory responses, and glutamate dysregulation due to energy deprivation. 

Treating mitochondria in astrocytes can directly benefit neuronal survival because of neuron-astrocyte interdependence. To develop methods in a cell- and organelle-specific manner is a challenge. Several approaches such as recombinant viral vectors, nanoparticles, or specialized peptides [88, 152–156] have been developed. Using these approaches, evidence to conserve neurons via targeting astrocyte mitochondria has been collected in several disease models such as acute cortical lesions [157] β-amyloid-expressing Alzheimer's disease [87, 88, 158, 159], chronic pain [160], and spinal cord injury [161] and CNS injury [89, 162]. 

Based upon these encouraging results, further studies consisting of a cocktail of antioxidants, mtPTP modulators, and alternative energy substrates together with CD38 activators can be tested to establish the therapeutic value of conserving astrocyte mitochondria in various brain injury models. Isolation of functional and healthy mitochondria from endogenous or exogenous sources to transplant to the site of injury has become another topic of interest. 

The original inspiring data come from the cardiac field, in that pediatric patients with congenital myocardial disease upon transplantation of pectoral muscle mitochondria have shown instant improvement in clinical trials [163]. Similar studies investigating CNS-related diseases have yet to be conducted. However, encouraging observations from several animal studies [145, 164–167] provides a compelling rationale, such as the study showing that injecting isolated mitochondria into gliomas of living mice triggers a metabolic switch from glycolysis to aerobic respiration, which correlated with reduced tumor growth [168]. 

In a mouse model of stroke, transplanted mitochondria were taken up by neuronal cells, and astrocytes in the penumbra region were shown to deliver mitochondria to neurons. As a result, neuronal death was reduced, which was associated with improved motor and neurological function [145]. Mitochondrial delivery supplemented with PEP1, a peptide carrier to the medial forebrain bundle of a Parkinson's rat model, spared neurons in the substantia nigra and improved locomotor function [169]. In contrast, delivery of viable mitochondria to spinal cord injured animals maintained energetics but failed to spare tissue or improve functional recovery [166]. 

These results provide proof of the f principle that mitochondria are organelles that can be transferred from one organ to another and assume the role of performance required by the recipient tissue. Moreover, it can be exchanged and transferred between different cells to support function and survival. What the signals are that differentiate between the donor and recipient are currently not known. 

In summary, there are several important reasons why it is important to investigate astrocyte mitochondria as a therapeutic target. First, in the face of an acute injury such as a stroke, neurons are the first to die; hence the window of opportunity to protect neuronal mitochondria is very narrow from the clinical perspective. Second, astrocytes survive acute injury; hence, maintaining their beneficial nature provides sustained protection in addition to reduced injury onset. 

Third, because astrocytes integrate into many functional units and interact with most cellular and anatomical structures, the protective measures will act on a multitude of elements in addition to neurons. Finally, different protective measures specific to the course of disease pathology can be implemented as the need for prevention and protection progresses to the regeneration and recovery phases.

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