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Extracellular Mitochondrial Dysfunction in Cerebrospinal Fluid of Patients with Delayed Cerebral Ischemia after Aneurysmal Subarachnoid Hemorrhage

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Abstract

Background

Mitochondrial dysfunction is related to brain ischemic injury and neural cell death. However, little is known about the association between mitochondrial dysfunction of cerebrospinal fluid (CSF) and delayed cerebral ischemia (DCI) following subarachnoid hemorrhage (SAH). The objective of this study was to investigate whether extracellular CSF mitochondria might serve as a potential biomarker for DCI.

Methods

CSF samples were serially collected at 1, 3, and 5 days following SAH in 33 patients (DCI, n = 12; and non-DCI, n = 21) who underwent coil embolization. To monitor mitochondrial membrane potentials, JC-1 dye was used. The ratio (red/green) of JC-1 was considered as an indicator of intact mitochondrial membrane potential. Flow cytometry was done to analyze extracellular mitochondria particles and their possible cellular origins.

Results

DCI patients had lower JC-1 red/green ratios than non-DCI patients at 1 day (3.35 [3.20–3.75] vs. 3.70 [3.40–3.95] in non-DCI) and 3 days (4.65 [4.45–5.00] vs. 5.10 [4.65–5.30] in non-DCI) after SAH. At 5 days after SAH, JC-1 red/green ratio was significantly lower in DCI than that in non-DCI (3.05 [2.90–3.35] vs. 4.20 [4.10–4.50]; p < 0.01) patients. DCI patients had a higher percentage of vWF-positive mitochondria (40.10% [38.25%–44.90%] vs. 30.20% [25.70%–36.68%]) and a lower percentage of GLAST-positive mitochondria particles (26.85% [17.10%–30.00%] vs. 31.60% [26.70%–35.00%]) than non-DCI patients. However, there was no significant difference in CD45-positive (p = 0.369) or CD41/61-positive mitochondrial particles (p = 0.155) between the two groups of patients.

Conclusions

Mitochondrial membrane potential could be a marker of DCI. JC-1 ratios seemed to be able to predict future DCI onset. Further studies are needed to determine detailed mechanisms of extracellular mitochondria-mediated cell-to-cell signals in DCI.

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Acknowledgements

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Funding

This study received funding from the National IT Industry Promotion Agency (R-20190315-004075) and Hallym University Research Fund.

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Authors and Affiliations

  1. Institute of New Frontier Stroke Research, Hallym University College of Medicine, Chuncheon, Korea

    Dong Hyuk Youn, Bong Jun Kim, Youngmi Kim & Jin Pyeong Jeon

  2. Genetic and Research Inc, Chuncheon, Korea

    Jin Pyeong Jeon

  3. Department of Neurosurgery, Hallym University College of Medicine, 77 Sakju-ro, Chuncheon, 24253, Republic of Korea

    Jin Pyeong Jeon

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  1. Dong Hyuk Youn
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  2. Bong Jun Kim
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Correspondence to Jin Pyeong Jeon.

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This study was approved by the hospital institutional review board (No. 2016-3, 2017-9 and 2018-6).

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Youn, D.H., Kim, B.J., Kim, Y. et al. Extracellular Mitochondrial Dysfunction in Cerebrospinal Fluid of Patients with Delayed Cerebral Ischemia after Aneurysmal Subarachnoid Hemorrhage. Neurocrit Care 33, 422–428 (2020). https://doi.org/10.1007/s12028-019-00895-1

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