GrpEL1 regulates mitochondrial unfolded protein response after experimental subarachnoid hemorrhage in vivo and in vitro

Chao Ma; Bixi Gao; Zongqi Wang; Wanchun You; Zhengquan Yu; Haitao Shen; Xiang Li; Haiying Li; Xuwei Zhang; Zhong Wang; Gang Chen

Brain Research Bulletin (Apr 2022)

GrpEL1 regulates mitochondrial unfolded protein response after experimental subarachnoid hemorrhage in vivo and in vitro

Chao Ma,
Bixi Gao,
Zongqi Wang,
Wanchun You,
Zhengquan Yu,
Haitao Shen,
Xiang Li,
Haiying Li,
Xuwei Zhang,
Zhong Wang,
Gang Chen

Affiliations

Chao Ma: Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, China; Institute of Stroke Research, Soochow University, Suzhou, 215006, China
Bixi Gao: Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, China; Institute of Stroke Research, Soochow University, Suzhou, 215006, China
Zongqi Wang: Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, China; Institute of Stroke Research, Soochow University, Suzhou, 215006, China
Wanchun You: Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, China; Institute of Stroke Research, Soochow University, Suzhou, 215006, China
Zhengquan Yu: Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, China; Institute of Stroke Research, Soochow University, Suzhou, 215006, China
Haitao Shen: Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, China; Institute of Stroke Research, Soochow University, Suzhou, 215006, China
Xiang Li: Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, China; Institute of Stroke Research, Soochow University, Suzhou, 215006, China
Haiying Li: Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, China; Institute of Stroke Research, Soochow University, Suzhou, 215006, China
Xuwei Zhang: Department of Neurosurgery, Lianyungang Traditional Chinese Medicine Hospital, Lianyungang 222000, China; Correspondence to: Department of Neurosurgery, Lianyungang Traditional Chinese Medicine Hospital, 160 Chaoyang Middle Road, Lianyungang 222000, China.
Zhong Wang: Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, China; Institute of Stroke Research, Soochow University, Suzhou, 215006, China; Correspondence to: Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou 215006, China.
Gang Chen: Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, China; Institute of Stroke Research, Soochow University, Suzhou, 215006, China

Journal volume & issue: Vol. 181
pp. 97 – 108

Abstract

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Subarachnoid hemorrhage (SAH) is a hemorrhagic stroke disease with high mortality and disability rates. Neurological recovery in early brain injury (EBI) after SAH is a crucial stage to reduce complications and improve the prognosis of patients. The mitochondrial unfolded protein response (UPRmt) is an essential mitochondrial damage repair process, that degrades aggresomes formed by misfolded proteins. UPRmt is a response to cellular stress and enhances mitochondrial homeostasis. GrpEL1 is a nucleotide exchange factor that assists mtHSP70 in nonnative folding proteins in mitochondria. However, the role of UPRmt and GrpEL1 after SAH is unclear. Western blot, Immunofluorescence, Aggresome staining, JC-1 staining were conducted to detect UPRmt after SAH in vivo and in vitro. The results showed that the UPRmt-related proteins HSP60 and mtHSP70 did not change in the EBI after SAH in vivo and in vitro but increased in the isolated mitochondria. In vitro primary neurons treated with oxyhemoglobin (OxyHb) achieved the same result as MG132 induction, increasing neuron protein aggresomes. The expression of GRPEL1 was unchanged in total protein and mitochondrial protein by Western blot. Co-immunoprecipitation (Co-IP) experiments showed that the GRPEL1-mtHSP70 complex decreased after OxyHb treatment. After GRPEL1 overexpression, the GRPEL1-mtHSP70 complex increased, while aggresome in neurons decreased. JC-1 showed an increased mitochondrial membrane potential, ATP content increased, and Western blot analysis revealed decreased cleaved-Caspase 9, suggesting improved mitochondrial function. In conclusion, the reduced GrpEL1-mtHSP70 complex is an essential factor affecting UPRmt in EBI after SAH. Increasing GrpEL1 promotes GrpEL1 and mtHSP70 binding, promoting the neuronal mitochondrial homeostasis, and might be an essential clinical intervention target for EBI after SAH.

Published in Brain Research Bulletin

ISSN: 1873-2747 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.sciencedirect.com/journal/brain-research-bulletin

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