The mitochondria as a potential therapeutic target in cerebral I/R injury

Front. Neurosci., 2025 · DOI: 10.3389/fnins.2024.1500647 · Published: January 7, 2025

Simple Explanation

Ischemic stroke is a significant cause of mortality and disability, often treated by restoring blood flow to the brain. However, this reperfusion can lead to further neuronal damage. Impaired mitochondrial function is believed to contribute to this cerebral ischemia/reperfusion (I/R) injury. This review explores how mitochondria respond to cerebral I/R injury, focusing on changes in mitochondrial proteins, reactive oxygen species, calcium levels, inflammation, and quality control, using animal models as experimental conditions. The study summarizes recent advances in understanding mitochondrial dysfunction and its relationship to neuronal death after cerebral I/R injury, emphasizing the pathophysiological regulation of mitochondrial dysfunction.

Study Duration

Not specified

Participants

Animal models

Evidence Level

Review

Key Findings

1
Mitochondrial protein acetylation, particularly through enzymes like GCN5L1 and Sirt3, plays a significant role in neuronal activity and the pathophysiology of cerebral injury. Sirt3, for example, regulates processes such as mPTP opening, mitochondrial dynamics, and mitophagy, protecting mitochondrial function and preventing neuronal death in ischemic stroke.
2
Calcium ion (Ca2+) homeostasis is crucial for neurons, influencing neurotransmitter release, excitability, and cell survival. During ischemic stroke, excessive Ca2+ accumulation leads to mitochondrial dysfunction. The exact quantity of Ca2+ that must be taken up by the mitochondria before reaching a neurotoxic level in cerebral ischemia and reperfusion is unclear.
3
Cerebral I/R injury is associated with inflammation, triggered by endogenous molecules released from damaged mitochondria. These mitochondrial DAMPs (mtDNA, N-formyl peptides) activate the innate immune system, leading to inflammatory responses. The NLRP3 inflammasome, activated by mitochondrial activities, contributes to cytokine release and cell death.

Research Summary

Mitochondria, supplying most ATP through oxidative phosphorylation, produce mtROS byproducts that can act as molecular signals or cause cell death. Maintaining a healthy mitochondrial state involves mitochondrial biogenesis and balanced fission/fusion. Damaged mitochondria are removed by mitophagy, and mitochondria act as Ca2+ sensors. Dysfunctional mitochondrial processes are involved in cerebral I/R injuries, but drugs targeting mitochondria have had limited clinical benefit. Combining drugs and interventional therapies is likely the optimal strategy for ischemic treatment. Nanomedicine for brain delivery may improve ischemic stroke treatment by targeting mitochondrial function, offering opportunities for future clinical trials.

Practical Implications

Therapeutic Target Identification

Mitochondrial function is a key therapeutic target for treating cerebral I/R injury. Understanding mitochondrial dysfunction may lead to effective treatments.

Novel Therapeutic Design

New discoveries about mitochondrial function in cerebral I/R injury can be used to design novel therapies that hold promise for better outcomes.

Drug Delivery Improvement

Improving drug delivery to the brain via nanomedicine may enhance the effectiveness of stroke treatment by targeting mitochondrial function.

Study Limitations

1
Limited achievement of prior efforts targeting mitochondrial permeability transition pore, monoamines metabolism, oxidative stress.
2
Yawning gap between preclinical and clinical studies.
3
Therapeutic drugs for ischemic stroke treatment are always not delivered to the brain due to the presence of blood–brain barrier (BBB).

Your Feedback

Was this summary helpful?

Back to Neurology