Introduction of Mitochondrial Dysfunction in Ischemic Stroke

Mitochondria, the engine of the cell, are crucial for energy homeostasis. Thus inevitably involved in ischemic neuronal death. During ischemia, decreased blood flow interrupts energy and ATP production. Besides energy generation, mitochondria regulate cell death mechanisms such as apoptosis and autophagy. That this mitochondrial damage kills neurons is one hallmark of ischemia/reperfusion injury. This means that mitochondrial repair is needed for the survival of cells and neurological repair following ischemia, and so mitochondrial targeting becomes an attractive treatment for ischemic stroke.

Fig.1. Mitochondria as a therapeutic target for ischemic stroke. (He, et al., 2020)

Ace Therapeutics provides reliable cell-based assay services to assess the effects of stroke drugs on mitochondrial activity and mitochondria-associated cell death.

• Mitochondrial membrane depolarization assay
• Mitochondrial superoxide generation detection
• Mitochondrial calcium ion detection
• Mitochondrial membrane permeability transition pore detection

Related Services

• Cell-Based Mitochondrial Function Assay Services for Stroke Drug Discovery
• Pathogenic Mechanism Analysis Services for Stroke

Mitochondrial Quality Control and Stroke

Mitochondria Quality Control Systems

Damage to mitochondria is a major source of stroke injury. Mitochondrial quality control (MQC) is necessary to reestablish mitochondrial homeostasis and mitigate stroke pathology. MQC includes mitochondrial fission and fusion, biogenesis, and mitophagy, all of which help keep mitochondria intact, stable, and functional. Such processes are crucial resistance mechanisms in order for the cells to survive mitochondrial damage.

Mitochondrial Dynamics and Stroke

In mitochondrial dynamics, mitochondrial fusion and division are dynamic processes that maintain homeostasis within cell networks through constant fusion-division and, thus, maintain normal physiological functions. Mitochondrial dynamics are closely associated with various pathophysiological mechanisms of post-stroke brain injury, including 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.

Targeting mitochondrial dynamics could be a promising strategy for treating ischemic stroke. Nevertheless, excessive mitochondrial fragmentation is detrimental, so therapeutic approaches should focus on inhibiting excessive division and restoring normal mitochondrial function.

Fig.2. Relationship between mitochondrial fusion/fission in stroke. (Tian, et al., 2022)

The Role of Mitophagy in Cerebral Ischemia

Mitophagy is the autophagy that purges injured mitochondria so that the mitochondria can be repaired and homeostasis restored. Mitophagy in ischemic stroke could be solely managed by PINK1/Parkin pathway. The role of mitophagy in ischemic brain injury remains disputed, though. Mitophagy is a twin-edged weapon, protective and destructive after an experimental stroke. On the one hand, it modulates stress by deleting damaged mitochondria and suppressing cell death signals, so it's a potential drug target. But if too much mitophagy is being stimulated, it can actually kill cells, so the impact may be different for different amounts. Subtle mitophagy helps neuronal survival; suffocating mitophagy can exacerbate ischemic brain injury. We'll have to learn more before we know if mitophagy is good or bad after a stroke.

Fig.3. Overview of mitophagy. (Tian, et al., 2022)

Mitochondrial Biogenesis in Stroke

Mitochondrial biogenesis is the creation of new mitochondria by the growth and division of existing mitochondria. It sets off a mass of mitochondrial growth. The endogenous neuroprotective mechanism called mitochondria biogenesis generates new functioning mitochondria when ischemia and hypoxia of strokes strike the body. We need more research to fully disentangle the molecular basis of mitochondrial biogenesis after stroke. Additional studies are necessary to examine the role of mitochondrial turnover, mechanisms of mitochondrial fusion and fission, and alternative transcriptional pathways after ischemia. The identification of new therapeutic targets that promote autophagy and mitochondrial biogenesis will be necessary in order to enhance mitochondrial maintenance.

Fig.4. Overview of mitochondrial biogenesis. (Tian, et al., 2022)

Intercellular Mitochondrial Transfer in Stroke

Damaged cells produce phosphatidylserine, which induces tunneling nanotube (TNT) formation promoting mitochondrial transfer. Intercellular mitochondrial transfer between different cell types is a promising approach for stroke treatment. Astrocytes, for example, in a model of temporary focal cerebral ischemia have been shown to pass their mitochondria to their neighbors, increasing cell survival signals, and the switch enhances neuronal recovery following stroke. The team also measured mitochondrial transfer in neuron-glia crosstalk and how it happens in primary cultured mouse cortical neurons damaged by different types of ischemia. Neuronal mitochondria serve as "life-saving" signals between neurons and astrocytes in the context of ischemic stress.

Promoting intercellular mitochondrial transfer by accelerating neuronal release or astrocyte phagocytosis may be a potential therapeutic strategy for the future treatment of ischemic stroke.

Fig.5. Intercellular mitochondrial transfer. (Liu, et al., 2018)

1. He, Z., et al. (2020). Mitochondria as a therapeutic target for ischemic stroke. Free Radical Biology and Medicine, 146, 45-58.
2. Tian, H., et al. (2022). Mitochondrial quality control in stroke: From the mechanisms to therapeutic potentials. Journal of cellular and molecular medicine, 26(4), 1000-1012.
3. Liu, F., et al. (2018). Mitochondria in ischemic stroke: new insight and implications. Aging and disease, 9(5), 924.