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The Mfn1-βIIPKC Interaction Regulates Mitochondrial Dysfunction via Sirt3 Following Experimental Subarachnoid Hemorrhage

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Abstract

Neuronal injury following subarachnoid hemorrhage (SAH) has been shown to be associated with mitochondrial dysfunction and oxidative stress. βIIPKC, a subtype of protein kinase C (PKC), accumulates on the mitochondrial outer membrane and phosphorylates mitofusin 1 (Mfn1) at serine 86. Here, we investigated the role of Mfn1-βIIPKC interaction in brain damage and neurological function in both in vivo and in vitro experimental SAH models. The expression of βIIPKC protein and the interaction of Mfn1-βIIPKC were found to be increased after OxyHb treatment in primary cultured cortical neurons and were also observed in the brain following SAH in rats. Treatment with the βIIPKC inhibitor βIIV5-3 or SAMβA, a peptide that selectively antagonizes Mfn1-βIIPKC association, significantly attenuated the OxyHb-induced neuronal injury and apoptosis. These protective effects were accompanied by inhibited mitochondrial dysfunction and preserved mitochondrial biogenesis. The results of western blot showed that βIIV5-3 or SAMβA markedly increased the expression of Sirt3 and enhanced the activities of its downstream mitochondrial antioxidant enzymes in OxyHb-treated neurons. Knockdown of Sirt3 via specific targeted small interfering RNA (siRNA) partially prevented the βIIV5-3- or SAMβA-induced protection and antioxidative effects. In addition, treatment with βIIV5-3 or SAMβA in vivo was found to obviously reduce brain edema, alleviate neuroinflammation, and preserve neurological function after experimental SAH in rats. In congruent with in vitro data, the protection induced by βIIV5-3 or SAMβA was reduced by Sirt3 knockdown in vivo. In summary, our present results showed that blocking Mfn1-βIIPKC interaction protects against brain damage and mitochondrial dysfunction via Sirt3 following experimental SAH.

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Funding

This work was supported by the National Natural Science Foundation of China (No. 81701932, No. 81871589, and No. 82072168), the Major Scientific Research Project of Wuxi Health Commission (No. Z202001), the Translational Medicine Research Major Project of Wuxi Health Commission (No. ZH201901), the Clinical Medical Science and Technology Development Foundation of Jiangsu University (No. JLY20180028), the China Postdoctoral Science Foundation funded project (No. 2019M651803), the Key Scientific Research Project of Jiangsu Health Commission (No. K2019018), and the Logistics Scientific Research Project of PLA (No. CLB20J027).

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  1. Tao Chen and Yue Wang contributed equally to this work.

Authors and Affiliations

  1. Department of Neurosurgery, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, 210000, Jiangsu, China

    Tao Chen & Chun-Hua Hang

  2. Department of Neurosurgery, The 904Th Hospital of PLA, Medical School of Anhui Medical University, Wuxi, 214044, Jiangsu, China

    Tao Chen, Yue Wang & Yu-Hai Wang

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  1. Tao Chen
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Correspondence to Yu-Hai Wang or Chun-Hua Hang.

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Chen, T., Wang, Y., Wang, YH. et al. The Mfn1-βIIPKC Interaction Regulates Mitochondrial Dysfunction via Sirt3 Following Experimental Subarachnoid Hemorrhage. Transl. Stroke Res. 13, 845–857 (2022). https://doi.org/10.1007/s12975-022-00999-5

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