Astrocyte Mitochondria in White-Matter Injury Part 1
Apr 25, 2024
Abstract
This review summarizes the diverse structure and function of astrocytes to describe the bioenergetic versatility required of astrocytes that are situated at different locations. The intercellular domain of astrocyte mitochondria defines their roles in supporting and regulating astrocyte-neuron coupling and survival against ischemia.
The relationship between neuronal coupling and memory has always attracted much attention. Neuronal coupling refers to the connections and interactions between neurons through synapses, while memory is the ability of the human brain to store and recall information about certain events or activities after experiencing them.
The impact of neuronal coupling on memory is mainly reflected in the following aspects:
First, neuronal coupling can facilitate memory storage. During different learning or experience processes, after connections occur between neurons, these connections will be strengthened, promoting the transmission and storage of information between neurons. Therefore, when we need to recall an event we have experienced, the connections between these neurons can help us find relevant information more quickly and accurately, thereby enhancing memory storage.
Secondly, neuronal coupling can also speed up memory retrieval. When we need to recall an event, the coupling between neurons will be activated, allowing us to quickly extract relevant information and allow us to recall what we have experienced more clearly. Therefore, coupling between neurons can also help us retrieve and recall information more quickly.
In addition, neuronal coupling can promote long-term memory preservation. When we remember an event or piece of information, the coupling between neurons is strengthened and forms a way of long-term connection and storage. This connection not only ensures that information can be retrieved and recalled quickly in the short term but also allows the information to be preserved in long-term memory.
To sum up, the coupling between neurons has a very important impact on our memory. By strengthening the connections between neurons, we can store and retrieve information more quickly, accurately, and long-term, helping us better cope with the challenges we encounter in learning, work, and life. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory because Cistanche deserticola is a traditional Chinese medicinal material that has many unique effects, one of which is to improve memory. The efficacy of Cistanche deserticola comes from the multiple active ingredients it contains, including tannic acid, polysaccharides, flavonoid glycosides, etc. These ingredients can promote brain health through a variety of pathways.
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The heterogeneity of astrocyte mitochondria, and how subpopulations of astrocyte mitochondria adapt to interact with other glia and regulate axon function, require further investigation.
It has become clear that mitochondrial permeability transition pores play 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. Reactive oxygen species cause axonal degeneration and a reduction in axonal transport, leading to axonal dystrophies and neurodegeneration including Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and Huntington's disease.
Developing new tools to allow better investigation of mitochondrial structure and function in astrocytes and techniques to specifically target astrocyte mitochondria, can help to unravel the role of mitochondrial health and dysfunction in a more inclusive context outside of neuronal cells.
Overall, this review will assess the value of astrocyte mitochondria as a therapeutic target to mitigate acute and chronic injury in the CNS.
Keywords
Glial cells; Mitochondrial dynamics; Neurovascular injuries; Neurodegenerative diseases; Astroglial interactions; Axonal degeneration.
Introduction
Astrocytes are the most widely distributed glial cells in the Central Nervous System (CNS) and they are located throughout grey and white matter, underneath dura matter, and around cerebral vessels (Fig. 1).
Subsequently, astrocytes specialize in numerous key functions based upon their locations such as maintaining brain homeostasis, regulating the extracellular environment, forming and maintaining the blood-brain barrier (BBB) and neurovascular unit (NVU) [1], adjusting cerebral blood flow [2–4], and regulating pH [5].
Because astrocytes balance glutamate uptake and release, they monitor neuronal activity and synaptic function and tri-partite synapse to facilitate learning and memory [6]. Astrocytes can store glucose as glycogen, and maintain glycogen storage to convert it to lactate when there is low glucose or increased activity [7, 8] and shuttle lactate to support neuronal and glial metabolism [9–11].
Controlling ATP release [12] and Ca2+ networking, astrocytes adjust the sleep-wake cycle [13], and facilitate the transfer and exchange of soluble substrates between cerebrospinal fluid and interstitial fluid [14–16]. Astrocytes also actively modulate axon conduction [17] as well as the formation and pruning of synapses [18, 19].
This vast functional repertoire is even more augmented in the human brain due to the significant complexity of human astrocytes compared to rodents [20]. This increased intricacy of human astrocytes, together with oligodendrocytes and expansion of white-matter volume [21], are proposed to be among the prominent reasons for higher cognitive function in humans compared to rodents.
Because astrocytes integrate into many units serving a specialized function in the brain, it is expected that astrocytes structurally adapt to their location and function [22]. In the CNS, astrocytes are derived mainly from radial glial cells and some from progenitor cells in the spinal cord [23–26], while there is a continuous generation of astrocytes in the adult brain in subventricular cells [25].
Astrocyte origin may also contribute to the morphological heterogeneity and the anatomical destination of the astrocyte, which eventually determines its function.
In agreement with this concept, transplantation of astrocytes derived from human immature glial progenitor cells into rodent brains resulted in the formation of astrocytes with the complex morphological complexity of the human brain, suggesting that the size and structural architecture of astrocytes are intrinsic to their cell origin [6]. Interestingly, these cells assumed characteristics of their location and function, demonstrating the conducive nature of astrocytes to adaptation [6].
Astrocytes show remarkable differences between brain regions [22]. For example, astrocytes exhibit distinct differences between gray and white matter [22]. Based upon morphological characteristics, astrocytes are named protoplasmic astrocytes in gray matter and fibrous astrocytes in white matter [1] (Fig. 1). Fibrous astrocytes are characterized by their smaller nuclei, and they extend their branches along the axons in parallel, giving them an elongated morphology [1].
Fibrous astrocytes contain larger amounts of filaments than protoplasmic astrocytes [27] to structurally support their elongated and extended branches [28–30]; therefore, Glial Acidic Fibrillary Protein (GFAP) is more prominent in these cells.
Protoplasmic astrocytes are larger with fine elaborate branches distributed around the cell body, achieving their characteristic "star-like" shape. Interestingly, this location-dependent specificity of astrocytes is equally well-preserved in the human brain, except that they are bigger, and protoplasmic astrocytes have more complex architectural detail [31].
Consequently, the participation of astrocytes in the tripartite synapse is enhanced in the human brain. In agreement with diverse morphology reflecting diverse functions, protoplasmic and fibrous astrocytes have different protein expression profiles. For instance, the cluster of differentiation 44 (CD44; [32] filamentous proteins such as vimentin and GFAP [33] are abundantly expressed by fibrous astrocytes in white matter.
The majority of gray-matter astrocytes do not express GFAP [34, 35] unless there is an injury.
Expression levels of GFAP are important in that they enable fast repetitive vs. longer but high-fidelity signal conduction in gray matter and white matter, respectively. CD44, on the other hand, is a hyaluronan receptor, suggesting an important interaction between white-matter astrocytes and the extracellular matrix.
Astrocytes also regulate glutamate homeostasis. Gray-matter astrocytes express five major glutamate transporters, while white-matter astrocytes express only GLT-1 and GLAST [36–38].
Even though expression levels of glutamate transporters are higher in white-matter astrocytes [37], the activity of glutamate transporters is seemingly higher in gray matter due to the higher numbers of synapses [39].
Given the abundant synapse numbers in the cortex, for instance, glutamate transport activity is highest in the corpus callosum [39]. Together with the increased capacity for glutamate-to-glutamine cycling in white-matter astrocytes, the need for more effective glutamate clearance becomes apparent to keep glutamate levels at approximately half of gray-matter levels [39].
Excitotoxicity to oligodendrocytes via activation of AMPA and Kainate receptors [40–48], but not NMDA receptors [49], highlights the importance of glutamate clearance by astrocytes in white matter to preserve oligodendrocyte-axon interactions and to sustain conduction. Activation of a variety of receptors on the astrocyte cell membrane triggers Ca2+ release from internal stores, which can spread to nearby astrocytes and initiate a Ca2+ wave [50] across astrocytes that propagates via gap junctions through an intricate network [51–53] to deliver a fast-long-distance signal.
Astrocytes have non-overlapping domains [35] but act in unison to recruit nearby astrocytes due to their gap junctions. Interestingly, this recruitment reaches a diameter of ~400 μm in gray matter, encompassing ~100 astrocytes. This network is shown to be most elaborate in the optic nerve due to the high coupling of astrocytes [54], although the functional correlation remains unknown. In addition, Na+ signaling plays an important role in maintaining astrocytic homeostasis.
Of note, the concentration of cytosolic Na+ in astrocytes is typically higher than in neurons [1, 55] and the influx of Na+ in astrocytes propagates from processes to soma and into adjacent cells through gap junctions [55–57].
Na+ can enter astrocytes through either cationic channels (e.g P2X and NMDA receptors, TRP channels, and specific Na+ called Nax channels) or Na+-dependent transporters (e.g. excitatory amino acid transporters types 1 and 2, GABA transporter type 1 and 3, glycine transporters type 1, noradrenaline and dopamine transporters, and Na+-coupled neutral amino acid transporters) [1, 58, 59].
The majority of plasmalemma transporters not only act as sensors but also modifiers of cytosolic Na+ [1]. On the other hand, Na+/K+ ATPase (NKA) is mainly responsible for the release of Na+ from astrocytes [60]. Astrocytic NKA has a lower affinity to K+ than in neurons because it contains α2 subunits instead of α1 and α3 subunits in neurons [61, 62].
Therefore, astrocytic NKA is important for sensing and maintaining the K+ balance. Also, by buffering K+ during neuronal activity, NKA plays an important role in the production of lactate production in astrocytes [63–65]. Additionally, astrocytes express all three subtypes of Na+/ Ca2+ exchanger (NCX) which is another important player in regulating Na+ [60, 66, 67].
Astrocytic NCX is sensitive to changes in the cytosolic concentration of Na+ and Ca2+ which is suitable for their role in preserving the astrocyte ionic homeostasis [68, 69]. In particular, astrocyte mitochondria express a unique version of the exchanger called NCLX which can exchange Li+ instead of Na+ and contribute significantly to maintaining mitochondrial function in astrocytes [70–72].
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