GDF11 alleviates secondary brain injury after intracerebral hemorrhage via attenuating mitochondrial dynamic abnormality and dysfunction

Anqi Xiao,Tao Li,Chao You,Xueqi Gan,Yanming Ren,Ruiqi Chen,Yiqi Zhang

doi:10.1038/s41598-021-83545-x

Abstract

Intracerebral hemorrhage (ICH) is a serious public health problem with high rates of death and disability. The neuroprotective effect of Growth Differentiation Factor 11 (GDF11) in ICH has been initially proved by our previous study. Oxidative stress (OS) plays crucial roles in mediating subsequent damage of ICH. However, whether and how mitochondrial dynamic events and function participated in ICH pathophysiology, and how mitochondrial function and OS interreacted in the neuroprotective process of GDF11 in ICH remains unclarified. Based on the rat model of ICH and in vitro cell model, we demonstrated that GDF11 could alleviate ICH induced neurological deficits, brain edema, OS status, neuronal apoptosis and inflammatory reaction. In addition, mitochondrial functional and structural impairments were obviously restored by GDF11. Treatment with antioxidant protected against erythrocyte homogenate (EH) induced cell injury by restoring OS status and mitochondrial fusion fission imbalance, which was similar to the effect of GDF11 treatment. Further, inhibition of mitochondrial division with Mdivi-1 attenuated mitochondrial functional defects and neuronal damages. In conclusion, our results for the first time proposed that GDF11 protected the post-ICH secondary injury by suppressing the feedback loop between mitochondrial ROS production and mitochondrial dynamic alteration, resulting in attenuated mitochondrial function and amelioration of neural damage.

Highlights

Intracerebral hemorrhage (ICH) is a serious public health problem with high rates of death and disability
As mitochondrial functions are deeply involved in secondary ICH injury, we evaluated mitochondrial function by measuring key enzyme activity associated with respiratory chain and adenosine triphosphate (ATP) levels
These results indicated that the antioxidant effect of NAC played neuroprotective role in erythrocyte homogenate (EH) induced cell injury by inhibiting reactive oxygen species (ROS) production, mitochondrial functional and structural impairments, which was similar to the effect of rGDF11 treatment

Summary

Introduction

Intracerebral hemorrhage (ICH) is a serious public health problem with high rates of death and disability. Treatment with antioxidant protected against erythrocyte homogenate (EH) induced cell injury by restoring OS status and mitochondrial fusion fission imbalance, which was similar to the effect of GDF11 treatment. Our results for the first time proposed that GDF11 protected the post-ICH secondary injury by suppressing the feedback loop between mitochondrial ROS production and mitochondrial dynamic alteration, resulting in attenuated mitochondrial function and amelioration of neural damage. Mitochondrial dysfunction may contribute to the deficiency of adenosine triphosphate (ATP) generation and result in further excessive ROS generation and neuronal apoptosis and aggravation of brain injury after ICH12,13. For mitochondrial dynamic properties are essential for neuronal activity[19], imbalance of fusion and fission could result in aberrant distribution of mitochondria and defective cellular function[20,21]. Hitherto, whether and how mitochondrial dynamic balance involves in ICH pathophysiology remains unexplored

Methods

Results

Conclusion