Autophagy Inhibition Reduces Irradiation-Induced Subcortical White Matter Injury Not by Reducing Inflammation, but by Increasing Mitochondrial Fusion and Inhibiting Mitochondrial Fission

Yafeng Wang,Tao Li,Yiran Xu,Xiaoli Zhang,Cuicui Xie,Xiaoyang Wang,Yong Wang,Juan Song,Kai Zhou,Changlian Zhu,Shan Zhang

doi:10.1007/s12035-021-02653-x

Abstract

Radiotherapy is an effective tool in the treatment of malignant brain tumors, but irradiation-induced late-onset toxicity remains a major problem. The purpose of this study was to investigate if genetic inhibition of autophagy has an impact on subcortical white matter development in the juvenile mouse brain after irradiation. Ten-day-old selective neural Atg7 knockout (KO) mice and wild-type (WT) littermates were subjected to a single 6-Gy dose of whole-brain irradiation and evaluated at 5 days after irradiation. Neural Atg7 deficiency partially prevented myelin disruption compared to the WT mice after irradiation, as indicated by myelin basic protein staining. Irradiation induced oligodendrocyte progenitor cell loss in the subcortical white matter, and Atg7 deficiency partly prevented this. There was no significant change between the KO and WT mice in the number of microglia and astrocytes in the subcortical white matter after irradiation. Transcriptome analysis showed that the GO mitochondrial gene expression pathway was significantly enriched in the differentially expressed genes between the KO and WT group after irradiation. Compared with WT mice, expression of the mitochondrial fusion protein OPA1 and phosphorylation of the mitochondrial fission protein DRP1 (P-DRP1) were dramatically decreased in KO mice under physiological conditions. The protein levels of OPA1and P-DRP1 showed no differences in WT mice between the non-irradiated group and the irradiated group but had remarkably increased levels in the KO mice after irradiation. These results indicate that inhibition of autophagy reduces irradiation-induced subcortical white matter injury not by reducing inflammation, but by increasing mitochondrial fusion and inhibiting mitochondrial fission.

Highlights

Radiotherapy is an effective method for the treatment of malignant brain tumors in children; the tumor cells are killed, such treatments can damage normal brain tissue [1]
We found that selective neural autophagy inhibition reduced irradiation-induced subcortical white matter injury not by reducing inflammation, but by increasing mitochondrial fusion and inhibiting mitochondrial fission
Subcortical white matter volume was assessed as the myelin basic protein (MBP)-positive volume, and the volume was significantly reduced in WT mice (0.90 ± 0.04 mm3) after irradiation compared to Atg7flox/flox; Nes−Cre knockout (Atg7 KO) mice (1.14 ± 0.06 mm3) (p = 0.037) (Fig. 1b)

Summary

Introduction

Radiotherapy is an effective method for the treatment of malignant brain tumors in children; the tumor cells are killed, such treatments can damage normal brain tissue [1]. A recent study showed that autophagy inhibitors could significantly alleviate the radiation-induced cerebral capillary damage and prolong the survival time in zebrafish larvae [7]. Another study found that radiation exposure led to the activation of autophagy in rat hippocampal neurons, and excessive activation of autophagy might damage synaptic plasticity by mediating synaptic vesicle degradation [8]. These studies provide evidence that excessive autophagy leads to capillary or synapse damage after irradiation, and autophagy inhibition might be a therapeutic target for irradiation-induced white matter injury. How deficiency in autophagy prevents white matter injury after irradiation is still not clear, and further research is needed

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