The crosstalk between chaperone-mediated autophagy and apoptosis via ATM/p53-mitochondria-dependent signaling contributed to ischemia-induced cerebral injuries

Stroke is the second leading cause of death and a leading cause of disability worldwide. Neuronal loss is a significant factor in determining the outcome of ischemic stroke. However, there is no effective treatment for neuronal loss caused by stroke. This study found that acute ischemia upregulated chaperone-mediated Autophagy (CMA) levels in both in vivo and in vitro models. Further, it was observed that inhibition of CMA with pharmacological intervention or LAMP2A knockdown (KD) ameliorated neuronal loss induced by acute ischemia. In addition, inhibition of CMA before or upon acute ischemia can significantly reduce the infarct size and restore neurological function, indicating that a CMA-targeted strategy may facilitate the outcomes of acute ischemic stroke. Notably, pharmacological intervention for CMA under normoxia conditions did not significantly affect neuronal survival. Meanwhile, intervention to CMA upregulation upon the acute ischemia may prevent the decreased CMA in the recovery stage of cerebral ischemia. Moreover, since mitochondrial dysfunction plays a vital role in the initiation and activation of Apoptosis, the role of CMA in neuronal mitochondrial function was observed with MitoSOX and TMRM staining. It was found that CMA upregulation contributed to oxygen-glucose deprivation (OGD)-induced mitochondrial injuries. Based on the reported association between ataxia telangiectasia mutated (ATM)-mitochondria signaling and p53 in the occurrence of Apoptosis, the activation of p53 was evidenced as the downstream event of the ATM-mitochondria signaling and played a vital role in Apoptosis upon OGD. Our current study indicates that there is crosstalk between Autophagy and Apoptosis. These findings highlight the critical role of CMA in the outcomes of ischemic stroke and implicate its potential application in stroke therapy.

ATM; CMA; Ischemic stroke; Macroautophagy; Neuron survival.