Role of Astrocytic Mitochondria in Limiting Ischemic Brain Injury?

Abstract

Until recently, astrocyte processes were thought to be too small to contain mitochondria. However, it is now clear that mitochondria are found throughout fine astrocyte processes and are mobile with neuronal activity resulting in positioning near synapses. In this review, we discuss evidence that astrocytic mitochondria confer selective resiliency to astrocytes during ischemic insults and the functional significance of these mitochondria for normal brain function.

FIGURE 1.

Schematic illustrating the response of astrocytic mitochondria to ischemia A: loss of oxygen and glucose leads to increased cytosolic Ca²⁺ concentrations that drives excessive accumulation of Ca²⁺ into the mitochondria via voltage-dependent anion channels (VDACs) and mitochondrial calcium uniporters (MCUs), triggering opening of the large mitochondrial permeability transition pore (MPTP). This allows the indiscriminate passage of small solutes out of the mitochondria causing dissipation of the mitochondrial membrane potential (ψ_m), which can culminate in release of cytochrome c and cellular apoptosis or membrane potential recovery with cell survival. B: mitochondria undergo morphological and network architectural changes in response to ischemia. They can adopt rounder discrete shape via fission mediated by dynamin-related protein 1 (Drp1) and fission protein 1 (Fis1), or form elongated, tubular interconnected network via fusion mediated by the outer membrane GTPases mitofusin-1 and -2 (MFN1/MFN2) and the inner membrane protein optic atrophy 1 (OPA1). C: astrocytes can promote neuronal survival by providing lactate as an energy substrate via monocarboxylate transporters (MCT) to neurons in the setting of impaired oxidative phosphorylation, in addition to directly donating functional mitochondria via a CD38-dependent mechanism. D: astrocyte mitochondria are enriched within vascular endfeet and may play a central role in neurovascular coupling by regulating Ca²⁺ signals. E: mitochondria are heterogeneous in structure and function, which may contribute to astroglial diversity. A subpopulation of astrocytic mitochondria may also be selectively resilient to ischemia.

FIGURE 2.

Schematic illustrating astrocytes as central mediators of neurovascular coupling Neuronal activity causes release of glutamate, which is taken up by astrocytes, triggering a Ca²⁺ signal that may be propagated down to or separately occurs within the vascular endfeet. This endfoot Ca²⁺ signal stimulates release of vasoactive factors, namely arachidonic acid (AA) and its metabolites—prostaglandins (PGs), epoxyeicosatrienoic acids (EETs), 20-hydroxyeicosatetraenoic acid (20-HETE)—onto cerebral blood vessels, evoking dilatation or constriction. The direction of blood vessel caliber change may be modulated by the partial pressure of oxygen in the blood (Po₂) or magnitude of the Ca²⁺ signal. The uptake of glutamate by astrocytes causes the immobilization of mitochondria near glutamate transporters in the processes or endfeet via changes in the binding of the transport proteins Miro and Trak. Astrocytic mitochondria are important in the generation and shaping of Ca²⁺ signals and thus likely play a key role in the control of blood flow in response to neuronal activity.