Mitochondrial Dynamics: A Potential Therapeutic Target for Ischemic Stroke

Abstract

Stroke is one of the leading causes of death and disability worldwide. Brain injury after ischemic stroke involves multiple pathophysiological mechanisms, such as oxidative stress, mitochondrial dysfunction, excitotoxicity, calcium overload, neuroinflammation, neuronal apoptosis, and blood-brain barrier (BBB) disruption. All of these factors are associated with dysfunctional energy metabolism after stroke. Mitochondria are organelles that provide adenosine triphosphate (ATP) to the cell through oxidative phosphorylation. Mitochondrial dynamics means that the mitochondria are constantly changing and that they maintain the normal physiological functions of the cell through continuous division and fusion. Mitochondrial dynamics are closely associated with various pathophysiological mechanisms of post-stroke brain injury. In this review, we will discuss the role of the molecular mechanisms of mitochondrial dynamics in energy metabolism after ischemic stroke, as well as new strategies to restore energy homeostasis and neural function. Through this, we hope to uncover new therapeutic targets for the treatment of ischemic stroke.

Keywords: energy metabolism; ischemic stroke; mitochondrial dynamics; molecular mechanisms; therapeutic target.

FIGURE 1

Schematic diagram of mitochondrial dynamics. Mitochondrial fission is the division of mitochondria into two smaller mitochondria, and the dynamin-related GTPase Drp1 plays a crucial role in this process. Drp1 was recruited through four single-way transmembrane Drp1 receptors anchored on the outer mitochondrial membrane (OMM): mitochondrial fission factors (Mff), mitochondrial kinetic proteins 49 and 51(MiD49 and MiD51), and Fis1. Mitochondrial fusion refers to the merging of two mitochondria into one. Mitofusin1 (Mfn1) and mitofusin2 (Mfn2) mediate mitochondrial outer membrane fusion, and optic atrophy protein 1 (Opa1) mediates the fusion of mitochondrial inner membrane.

FIGURE 2

Energy metabolism in the brain. The uptake and utilization of glucose by cells in the brain requires the neurovascular unit, which is composed of brain capillary endothelial cells, pericytes, astrocytes, oligodendrocytes, microglia, and neurons. Glucose enters cells through specific glucose transporters (GLUTs), such as GLUT1, GLUT2, and GLUT7 in astrocytes, GLUT1 in oligodendrocytes, and GLUT3 and GLUT4 in neurons. Numerous metabolic intermediates formed by glucose in the brain can also be oxidized to produce energy, such as lactate, pyruvate, and glutamate. The dynamic regulatory mechanism of lactic acid metabolism between astrocytes and neurons is known as the astrocyte–neuron lactate shuttle. Neurons release glutamate to stimulate glucose uptake by astrocytes. Astrocytes produce lactic acid by aerobic glycolysis in the cytoplasm and then transport to neurons.

FIGURE 3

Molecular mechanisms of mitochondrial dynamics in post-ischemic stroke injury. Cerebral ischemia and hypoxia lead to the imbalance of mitochondrial division and fusion, which is related to calcium overload, reactive oxygen species (ROS), mitochondrial permeability transition pores(MPTP), apoptosis, and mitophagy. MCU, mitochondrial calcium uniporter; NMPAR, N-methyl-D-aspartate receptors; AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors; [Ca²⁺] ext, calcium ion concentration in extracellular; [Ca²⁺] cyt, calcium ion concentration in cytoplasmic; [Ca²⁺] mit, calcium ion concentration in mitochondria.