Current views on the role of autophagy in the pathogenesis of acute ischemic stroke

Abstract

Acute ischemic stroke (IS) is an urgent medical and social challenge. Despite extensive studying the causes for acute cerebrovascular ischemia, the issues of early diagnosis, prevention, and prediction of IS outcome is still relevant. Elucidation of molecular mechanisms operating in the penumbra is of a great clinical interest for development of new diagnostic and therapeutic strategies. Of particular interest is neuronal death through autophagy and mitophagy (selective autophagy) noted to be activated after an ischemic attack. Experiments on animal models have shown that mitochondrial dysfunction is centrally involved in damage to neurons and microglial cells in acute IS. However, reports on the role of mitophagy in the pathogenesis of acute IS are inconsistent and scarce. The aim of this review was to analyze current experimental studies on molecular mechanisms and the patho- genetic role of mitophagy in modeled acute IS. The reviewed literature was obtained from international and Russian databases, including Scopus, Web of Science, Springer, and Russian Science Citation Index. This review characterizes the key mitochondrial proteins involved in signaling cascades of mitophagy in acute IS and shows that mitophagy plays a dual, Janus-faced role in the IS pathogenesis. Ineffective mitophagy contributes to the activation of NLRP3-inflammation in acute IS. while the pharmacological induction of basic mitophagy blocks the activation of NLRP3-inflammasome. The authors presented results of experimental pharmacological modulation of protective (basic) mitophagy in models of acute IS. The most promising strategy is to target signaling cascades that suppress NLRP3 inflammation and proteins inducing basic neuroprotective mitophagy. This review shows that mitophagy is actively involved in various stages of the pathogenesis of acute IS. Mitophagy is a promising therapeutic target provided it is properly modulated. However, clear understanding of the factors influencing the balance between basic (protective) and activated (pathological) mitophagy has not yet been achieved, and this issue requires further study.