Astrocyte Mitochondria in White-Matter Injury Part 4

Role of Astrocyte Mitochondria in Glial Cell Interactions and White-Matter Function

The role that dysfunctional mitochondria have in glial cell function, and its implications for neuronal homeostasis and white-matter function, have been largely understudied. One underlying reason is the misperception that because the white matter and glial cells are more resilient to injury compared to neurons, they do not die or sustain an injury. 

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Indeed, oligodendrocytes, astrocytes, and microglia do not degenerate upon impairment of mitochondrial function, as they rely primarily on glycolysis to produce energy and have a higher antioxidant capacity than neurons. However, oligodendrocytes, axons, and myelin sustain long-lasting injury due to changes in Ca2+ signaling, inflammation, and oxidative stress, resulting in impaired white-matter function. 

Moreover, recent evidence highlights the role of mitochondrial metabolism and signaling in glial cell function and nearby neuronal support. Table 1 provides an overview of key findings for the role of astrocyte mitochondria in physiological, pathophysiological state, or aging. 

Astrocytes and oligodendrocytes originate from the embryonic ectoderm, while microglia originate from the mesoderm and enter the vertebrate brain during embryogenesis. Advances in counting techniques have demonstrated that while the overall ratio of neurons to glial cells varies between different regions in the brain, a ratio of ~1:1 glia to neurons exists in the entire human brain [170]. 

Oligodendrocytes are responsible for axon myelination, providing axons with an "insulating coat" that enhances nerve impulse conduction interrupted at regular intervals by internodal segments of myelin separated by gaps (nodes of Ranvier) [171]. 

Oligodendrocytes are found in both gray matter and white matter, but they are a major fraction of all the cells in white matter. Microglial cells are resident macrophages distributed throughout the central nervous system (CNS) [172]. 

As innate immune cells, microglia are activated by infection, tissue injury, or xenobiotics. Upon activation, microglia retract their cytoplasmic extensions and migrate to the site of injury, where they proliferate and become antigen-presenting cells. In astrocytes, IFNγ stimulation increases the expression of MHCII, while endocytosis is inhibited to prolong surface retention of antigens [173]. 

Microglia phagocytose degenerating cells act as sources of immunoregulatory and neuromodulatory factors such as cytokines, chemokines, and neurotrophic factors. Microglia can be activated by cell-surface receptors for endotoxins, cytokines, chemokines, misfolded proteins, serum factors, and ATP. While mild activation is a key adaptive immune response, continuous activation or overactivation of microglia is thought to contribute to neurodegeneration [174–176]. 

Despite reports of apoptosis in astrocytes and microglia under different experimental conditions, there is little information regarding the loss or degeneration of these glial cells concerning human disorders. Conversely, oligodendrocytes are known to degenerate in demyelinating disorders such as multiple sclerosis and to be affected directly or indirectly by most known disorders in the CNS including ischemia, trauma, and neurodegeneration. 

Glutamate/Ca2+ excitotoxicity, inflammation (cytokines), and oxidative stress are common triggers for oligodendrocyte injury in these pathological situations. The high lipid and iron content of oligodendrocytes also makes them susceptible to oxidative damage induced by cytokines [177]. 

Importantly, mitochondrial respiration/metabolism seems to be primarily involved in oligodendrocyte differentiation, while glycolysis appears to be sufficient to maintain post-myelinated (differentiated) oligodendrocytes [178]. Accordingly, demyelination disorders linked to mitochondrial dysfunction seem to be primarily linked to increased oxidative damage and changes in Free Fatty Acid (FFA) metabolism, but not energy failure [179–181]. 

Dysfunction of glial mitochondria can be detrimental to white-matter function and can trigger and participate in various neurodegenerative diseases. The mitochondrial Ca2+ signaling pattern and the capacity to initiate and contribute to inflammation and oxidative stress together encompass major injury mechanisms contributing to various disease pathologies. However, very little is known about the impact of mitochondrial Ca2+ homeostasis on glial signaling. 

As in other cell types, functional mitochondria in astrocytes and oligodendrocytes regulate Ca2+ waves generated by the activation of inositol 1,4,5-triphosphate (IP3) receptors (IP3R) and the release of Ca2+ from the endoplasmic reticulum (ER) [182–184]. Mitochondrial Ca2+ has also been shown to regulate vesicular glutamate release from astrocytes, which modulates synaptic communication and excitability [185]. 

Ca2+ accumulation in mitochondria also modulates oxidative phosphorylation and energy production. Ca2+ release from the ER stimulates mitochondria-dependent energy production in astrocytes [186]. A recent report demonstrated that Ca2+ release via NCX is coupled to store-operated Ca2+ entry (triggered by Ca2+ depletion from ER stores) and regulates astrocyte proliferation and excitotoxic glutamate release [72, 187, 188]. 

Therefore, not only do mitochondria regulate Ca2+ accumulation and dynamics, but also its release. Ultrastructural analysis has revealed that mitochondria of white-matter astrocytes are more elongated than those in gray-matter astrocytes [189], but how this contributes to cell-to-cell interaction and function is yet to be explored. 

Note that in addition to its local impact, astrocyte networking can aggravate and disseminate mitochondrial Ca2+ signaling away from the center of injury, recruiting more cells and contributing to the progression of neurodegenerative diseases in white matter.

It has been established that mitochondrial dysfunction triggers inflammatory responses mainly due to changes in microglial mitochondrial metabolism following activation. Consequently, classic activation of microglia (M1-like phenotype) was recently reported to be paralleled by a metabolic switch from mitochondrial OXPHOS to glycolysis that enhances carbon flux to the Pentose Phosphate Pathway (PPP) [190–192]. 

Interestingly, inhibition of complex I activity activates microglial cells [193–195], while impairment of mitochondrial fission reduces the production of pro-inflammatory signals [196]. Induction of the M2-like phenotype results in no observable changes in mitochondrial oxygen consumption or lactate production [191]. However, mitochondrial toxins such as 3-nitro propionic acid and rotenone impair the transition to the M2-like phenotype induced by IL-4 [197]. 

These results suggest that mitochondrial dysfunction in microglia can exacerbate the pro-inflammatory M1 phenotype and result in the release of neurotoxic pro-inflammatory cytokines, and enhanced ROS/RNS formation [198]. Pro-inflammatory cytokines released from microglia also "activate" astrocytes, which might also produce TNFα to potentiate microglia activation. Inflammation is a key contributor to most neurological disorders. 

As a result, co-cultures of microglia and astrocytes produce more neurotoxic factors than either activated cell type alone [199]. Whether astrocytes can be activated in the absence of microglia is still unclear since most studies using primary cultures of astrocytes also contain at least 5% of microglia that significantly contribute to astrocyte activation [200, 201]. 

The enhanced resistance to oxidative damage in astrocytes is observed even though astrocyte mitochondria have deficient mitochondrial respiration and increased ROS formation when compared to neurons [202]. Interestingly, a comparative study demonstrated that astrocytes are more resistant to oxidative damage than microglia or oligodendrocytes [203]. 

Astrocytes contain higher levels of endogenous antioxidants and antioxidant systems that include NADPH and G6PD (glucose-6-phosphate dehydrogenase). The importance of astrocytes for neuronal redox homeostasis was established by a recent study demonstrating that conditional depletion of astrocytes promotes neuronal injury by oxidative stress [204]. 

This study raises the question of what is the role of mitochondria in redox homeostasis in astrocytes and neurons. The loss of GSH by its export to neurons or due to the detoxification of electrophiles is expected to prompt astrocytes to replenish GSH precursors. Interestingly, GSH depletion upregulates mitochondrial activity in astrocytes [205], but the exact mechanisms that regulate this phenomenon are still unclear. 

This brief overview of the role of mitochondria in glial cell function which includes metabolism, redox homeostasis, Ca2+ signaling, inflammation, and cell death, clearly indicates the importance of mitochondrial health in glial cells and its relevance to neuronal function. Yet, this review also highlights our limited understanding of mitochondria function in glial cells and the need for further investigations in this rapidly expanding area. 

Many questions remain to be answered regarding the role of mitochondria in neurological disorders, suggesting that it is time to think about mitochondrial health and dysfunction in a more inclusive context outside of neuronal cells. It has become clear that mitochondrial mtPTP plays a key role in a wide variety of human diseases whose common pathology may be based on mitochondrial dysfunction triggered by Ca2+ and potentiated by oxidative stress [206]. 

Reactive oxygen species cause axonal degeneration and a reduction in axonal transport, leading to axonal dystrophies and neurodegeneration including Alzheimer's disease [207], amyotrophic lateral sclerosis [208], Parkinson's disease [209], and Huntington's disease [210]. 

Given the importance of axonal transport for the preservation of axonal integrity, surprisingly little is known about how oxidative stress affects axonal transport, and whether this contributes to the damaging effects of elevated levels of ROS. Recent advances investigating small-molecule inhibitors for mtPTP represent compounds of high therapeutic value since mtPTP activation and opening form a shared target for numerous diseases [206]. 

Consequently, the search for targeted small-molecule therapeutics for some of the most widespread and therapeutically challenging human diseases, such as multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's Disease, and stroke is advancing. 

For instance, ischemia-reperfusion injury is a key disorder in which mtPTP opening plays a prominent role in ischemic damage of any tissue, which is most pronounced in ischemic damage of the heart and brain. Excitotoxicity, which is a major pathway of ischemia-reperfusion injury, is characterized by the excessive entry of Ca2+ into neurons that can be primarily triggered by glutamate and NMDA receptor activation inducing mtPTP opening. 

Alzheimer's disease is the most common form of mental disability in the elderly and the merging of various mechanisms leading to Ca2+ dyshomeostasis activates mtPTP, initiating the apoptosis of neurons and nearby cells. 

Dopaminergic neurons are distinctively reliant on voltage-dependent L-type Ca2+ channels for independent pacemaking activity and tonic dopamine release [211]. Consequently, these cells are particularly vulnerable to perturbations in the Ca2+ buffering capacity of mitochondria, which lead to mtPTP opening in Parkinson's patients. Huntington's disease, a progressive genetic disorder that results in motor, cognitive, and psychiatric disturbances caused by mutations in the gene encoding huntingtin (Htt) that ultimately leads to death in adulthood, is another example that appears to involve mtPTP-dependent mitochondrial defects in its pathogenesis. 

In amyotrophic lateral sclerosis, affected motor neurons show mitochondrial swelling and fragmentation, and mitochondrial Ca2+ induces abnormal membrane depolarizations that lead to mtPTP opening. 

Multiple sclerosis is the most common disabling disease of young and middle-aged adults, and axonal degeneration is a critical part of the pathogenesis of MS and a major determinant of permanent disability. Axoplasmic Ca2+ overload driven by ionic imbalances and ROS is postulated to lead to mitochondrial dysfunction and result in pathologic opening of the PTP, which ultimately may be critical to axonal degeneration in MS [211]. 

Therefore, there is a long list of human pathologies in which such mtPTP inhibitors may play a crucial role. Note that contributing mitochondrial dysfunction has conventionally been attributed to neurons and axons. 

The importance of glia-axon interactions in terms of metabolism, signaling, and function is now recognized, but questions as to what the role of astrocyte mitochondria is in the pathogenesis of these diseases currently remain unanswered. Future research addressing these questions will reveal a better understanding of neurodegenerative diseases and identify novel therapeutic targets.

Acknowledgments

This work was supported by grants from the National Institute of Aging (NIA, AG033720) and the National Institute of Neurological Diseases (NINDS, NS094881) to S.B. We thank Dr. Chris Nelson for helping edit this paper.

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