Mitochondrial Dynamics: A Potential Therapeutic Target for Ischemic Stroke

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Mitochondrial Dynamics: A Potential Therapeutic Target for Ischemic Stroke

Xiangyue Zhou¹, Hanmin Chen¹, Ling Wang², Cameron Lenahan³, Lifei Lian⁴, Yibo Ou¹ and Yue He^1*

• ¹Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
• ²Department of Operating Room, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
• ³Department of Biomedical Sciences, Burrell College of Osteopathic Medicine, Las Cruces, NM, United States
• ⁴Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

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.

Introduction

Stroke is an acute cerebrovascular disease resulting in cerebral blood circulation disorders due to the sudden rupture or occlusion of blood vessels in the brain. Stroke is associated with high morbidity, mortality, and rates of disability (GBD 2016 Stroke Collaborators, 2019), and can be classified as either ischemic or hemorrhagic. Currently, stroke has become the second leading cause of death globally (Lindsay et al., 2019), and is the primary cause of death in China (Wang Y. et al., 2020). It has been a difficult endeavor to save more lives and improve neurological recovery after stroke. As such, this challenge emphasizes the growing need for therapeutic agents that can mitigate brain injury and promote neurological recovery after stroke.

Energy metabolism is an important basis for cellular function, as it is the process by which cells utilize nutrient substances, such as sugars and fats, and produce adenosine triphosphate (ATP). Additionally, ATP is broadly used in cellular activities, and is necessary for ensuring a normal cell lifespan. Mitochondria, which are commonly considered the powerhouse of the cell, are a major site of oxidative metabolism in eukaryotes, and are where sugars, fats, and amino acids are ultimately oxidized to release energy (Cardoso et al., 2010). The state of cellular energy metabolism is closely associated with mitochondrial dynamics, which refers to the dynamic process of mitochondrial fusion and division. Mitochondria maintain a steady state in the mitochondrial network through continuous fusion-division, thus maintaining the normal physiological function of cells (Dorn and Kitsis, 2015). Mitochondrial dynamics are involved in the formation and regulation of mitochondrial permeability transition pores (MPTPs), reactive oxygen species (ROS), and neuronal apoptosis (Roy et al., 2015). Mitochondrial dynamics can affect energy metabolism and post-stroke neuronal function by regulating the number, morphology, and function of mitochondria.

To identify potential interventional targets and novel diagnostic methods, it is crucial to understand the molecular mechanisms, especially those of mitochondrial dynamics after ischemic stroke. Herein, we will discuss the role of mitochondrial dynamics, as well as the energy metabolism involved in ischemic stroke. Moreover, an improved understanding of how mitochondrial dynamics affect energy metabolism will provide opportunities for the development of new therapeutic strategies targeting mitochondrial fusion and division after ischemic stroke.

Mitochondrial Dynamics and Energy Metabolism in the Brain

Cell energy metabolism refers to the metabolic pathway of ATP synthesis associated with nicotinamide adenine dinucleotide (NADH) turnover (Rigoulet et al., 2020). This pathway mainly includes the decompositional metabolism of sugar (aerobic oxidation, glycolysis, and phosphate sugar pathway), the tricarboxylic acid (TCA) cycle, fatty acid oxidation and synthesis, amino acid metabolism, and vitamin metabolism. Mitochondria are “energy factories” in eukaryotic cells, and are key sites of oxidative phosphorylation. Mitochondria are organelles that are present in most cells and are coated by two layers of membrane. Mitochondria can be divided into four functional regions: the outer mitochondrial membrane (OMM), intermembrane space (IMS), inner mitochondrial membrane (IMM), and mitochondrial matrix (listed in order from outside to inside). The proton concentration gradient originating from the electron transport chain in the IMM drives ATP generation (Scheffler, 2001). Moreover, mitochondria are highly mobile. Mitochondrial dynamics include fusion, division, selective degradation, and transport processes. Dynamic changes in mitochondria are important for immunity, apoptosis, and the cell cycle. These dynamic transformations are mainly mediated by large GTPases that belong to the dynamin family (Tilokani et al., 2018). In addition to generating energy, mitochondria can also drive cell dysfunction or death either passively (through ROS toxicity) or actively (through programed necrosis and apoptosis). Mitochondrial division and fusion play central roles in these processes (Dorn and Kitsis, 2015).

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