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Loss of MIC60 Aggravates Neuronal Death by Inducing Mitochondrial Dysfunction in a Rat Model of Intracerebral Hemorrhage

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Abstract

Mitochondrial damage has been reported to be a critical factor for secondary brain injury (SBI) induced by intracerebral hemorrhage (ICH). MIC60 is a key element of the mitochondrial contact site and cristae junction organizing system (MICOS), which takes a principal part in maintaining mitochondrial structure and function. The role of MIC60 and its underlying mechanisms in ICH-induced SBI are not clear, which will be investigated in this present study. To establish and emulate ICH model in vivo and in vitro, autologous blood was injected into the right basal ganglia of Sprague–Dawley (SD) rats; and primary-cultured cortical neurons were treated by oxygen hemoglobin (OxyHb). First, after ICH induction, mitochondria were damaged and exhibited mitochondrial crista-structure remodeling, and MIC60 protein levels were reduced. Furthermore, MIC60 overexpression reduced ICH-induced neuronal death both in vivo and in vitro. In addition, MIC60 upregulation reduced ICH-induced cerebral edema, neurobehavioral impairment, and cognitive dysfunction; by contrast, MIC60 knockdown had the opposite effect. Additionally, in primary-cultured neurons, MIC60 overexpression could reverse ICH-induced neuronal cell death and apoptosis, mitochondrial membrane potential collapse, and decrease of mitophagy, indicating that MIC60 overexpression can maintain the integrity of mitochondrial structures. Moreover, loss of MIC60 is after ICH-induced reduction in PINK1 levels and mislocalization of Parkin in primary-cultured neurons. Taken together, our findings suggest that MIC60 plays an important role in ICH-induced SBI and may represent a promising target for ICH therapy.

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Data Availability

The datasets generated and/or analyzed during the current study are not publicly available due to the confidential policy of our hospital but are available from the corresponding author on reasonable request.

Abbreviations

ICH:

Intracerebral hemorrhage

SBI:

Secondary brain injury

MICOS:

Mitochondrial contact site and cristae junction organizing system

OxyHb:

Oxygen hemoglobin

BBB:

Blood–brain barrier

siRNA:

Small interfering RNA

PVDF:

Polyvinylidene difluoride

MPTP:

Mitochondrial permeability transition pore

MMP:

Mitochondrial membrane potential

ROS:

Reactive oxygen species

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Funding

This work was supported by the National Key R&D Program of China (No. 2018YFC1312600 and No. 2018YFC1312601), the National Natural Science Foundation of China (No. 81771255 and No.81830036 and No.81801151), the Natural Science Foundation of Jiangsu Province under grant (No. BK20180204), the Project of Jiangsu Provincial Medical Innovation Team (No. CXTDA2017003), the Project of Jiangsu Provincial Medical key Talent (No. ZDRCA2016040), Suzhou Science and Technology (No. SS2019056), Jiangsu Commission of Health (No. K2019001), Suzhou Key Medical Centre (No. Szzx201501), Suzhou Government (No. SYS2019045), and Postgraduate Research & Practice Innovation Program of Jiangsu Province (No. KYCX20_2694).

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  1. Ruming Deng and Wenjie Wang contributed equally to this work.

Authors and Affiliations

  1. Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, 215006, China

    Ruming Deng, Wenjie Wang, Xiang Xu, Jiasheng Ding, Jiahe Wang, Siyuan Yang, Haiying Li, Haitao Shen, Xiang Li & Gang Chen

  2. Department of Neurosurgery, The People’s Hospital of Bozhou, Bozhou, Anhui Province, China

    Ruming Deng

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Contributions

GC and XL participated in the design of this study. RD and WW performed the experiments and wrote the paper. XX and JD helped to design the analysis strategy and implement the analysis and constructive discussion. JW and YS helped conduct the literature review. HL and HS reviewed and edited the manuscript. All authors have critically revised the manuscript and approved the final version.

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Correspondence to Xiang Li or Gang Chen.

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All animal experiments are strictly in accordance with the guideline of Soochow University institutional Animal Care and Use Committee.

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Deng, R., Wang, W., Xu, X. et al. Loss of MIC60 Aggravates Neuronal Death by Inducing Mitochondrial Dysfunction in a Rat Model of Intracerebral Hemorrhage. Mol Neurobiol 58, 4999–5013 (2021). https://doi.org/10.1007/s12035-021-02468-w

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