Miro1 Regulates Neuronal Mitochondrial Transport and Distribution to Alleviate Neuronal Damage in Secondary Brain Injury After Intracerebral Hemorrhage in Rats

Abstract

Intracerebral hemorrhage (ICH) is a primary cause of death and disability in adults worldwide. Secondary brain injury (SBI) induced by ICH can lead to impaired mitochondrial function, which ultimately contributes to apoptosis and necrosis. Mitochondrial Rho GTPase 1 (Miro1) is a key regulator of mitochondrial movement and motor protein binding. Although Miro1 has been demonstrated to be implicated in various types of central nervous system damage, its potential effect on ICH-induced SBI has not been studied in detail. Hence, in the present new study, we explored the effect of Miro1 on SBI in vivo and in vitro. Self-body heart blood was injected into the right basal ganglia of the rat brain in vivo. Meanwhile, our in vitro model of ICH was based on the stimulation of oxygen hemoglobin (OxyHb) to neurons. Then, Miro1 was overexpressed both in the brains of rats after ICH in vivo and in OxyHb-treated cultured neurons in vitro. Miro1 overexpression in vivo reduced several pathological indexes such as brain edema, neurobehavioral impairment, and neuronal death. Immunofluorescent staining in vitro showed that overexpression of Miro1 ameliorated neuronal damage via facilitation of mitochondrial transport and distribution. JC-1 staining indicated that overexpression of Miro1 reduced the collapse of mitochondrial membrane potential and enhanced mitochondrial mass. Additionally, live-dead cellular staining and flow cytometry analysis revealed that Miro1 overexpression in cultured neurons reduced both necrotic and apoptotic rates. In contrast, inhibition of Miro1 expression yielded opposite effects to those of Miro1 overexpression. Above all, the upregulation of Miro1 significantly alleviated pathological symptoms on SBI in vivo and in vitro.

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Funding

This work was supported by National Key R&D Program of China (No. 2017YFC0110304 and 2018YFC1312600), National Natural Science Foundation of China (81571121), Project of Jiangsu Provincial Medical Innovation Team (No. CXTDA2017003), Jiangsu Provincial Medical Youth Talent (No. QNRC2016728), Suzhou Key Medical Centre (No. Szzx201501), Scientific Department of Jiangsu Province (No. BE2017656), the Natural Science Foundation of Jiangsu Province under grant (No. BK20180204 & No.BK20170363), Suzhou Science and Technology (NO. SS2019056), and Jiangsu Commission of Health (NO. K2019001).

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BL carried out the experiments. YZ participated in the design of the study and performed the statistical analysis. HL helped to draft the manuscript. HS participated in the acquisition of data. YW carried out analysis and interpretation of data. XL, GC (Gang Cui) and GC (Gang Chen) participated in the design of the study and drafted the manuscript. All authors read and approved the final manuscript.

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Correspondence to Xiang Li or Gang Cui.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals comply with the ethical standards of the Animal Ethics Committee of Suzhou University. This article does not contain any studies with human participants performed by any of the authors.

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Li, B., Zhang, Y., Li, H. et al. Miro1 Regulates Neuronal Mitochondrial Transport and Distribution to Alleviate Neuronal Damage in Secondary Brain Injury After Intracerebral Hemorrhage in Rats. Cell Mol Neurobiol (2020). https://doi.org/10.1007/s10571-020-00887-2

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Keywords

  • Miro1
  • Intracerebral hemorrhage
  • Mitochondria
  • Neuronal apoptosis