Targeting neuronal mitophagy in ischemic stroke: an update

Abstract

Cerebral ischemia is a neurological disorder associated with complex pathological mechanisms, including autophagic degradation of neuronal mitochondria, or termed mitophagy, following ischemic events. Despite being well-documented, the cellular and molecular mechanisms underlying the regulation of neuronal mitophagy remain unknown. So far, the evidence suggests neuronal autophagy and mitophagy are separately regulated in ischemic neurons, the latter being more likely activated by reperfusional injury. Specifically, given the polarized morphology of neurons, mitophagy is regulated by different neuronal compartments, with axonal mitochondria being degraded by autophagy in the cell body following ischemia–reperfusion insult. A variety of molecules have been associated with neuronal adaptation to ischemia, including PTEN-induced kinase 1, Parkin, BCL2 and adenovirus E1B 19-kDa-interacting protein 3 (Bnip3), Bnip3-like (Bnip3l) and FUN14 domain-containing 1. Moreover, it is still controversial whether mitophagy protects against or instead aggravates ischemic brain injury. Here, we review recent studies on this topic and provide an updated overview of the role and regulation of mitophagy during ischemic events.

Machine Learning Analysis of Gene Expression Profiles ofPyroptosis-Related Differentially Expressed Genes in IschemicStroke Revealed Potential Targets for Drug Repurposing

“…The AUROC value of 0.701 (Figure 4C) underscores BNIP3L's efficacy as a diagnostic marker, illuminating its role as a response mechanism to IS, aimed at safeguarding the ischemic brain region. Corroborating this, research by Li et al [63] indicates that BNIP3L knockout mice exhibit larger brain infarct areas and exacerbated neurological deficits, which can be ameliorated through BNIP3L overexpression. Consequently, compounds capable of stimulating BNIP3L expression offer promise as therapeutic agents against IS.…”

Mechanisms and therapeutic targets of mitophagy after intracerebral hemorrhage

“…Mitophagy is a selective autophagy that plays an important role in removing dysfunctional or damaged mitochondria to maintain mitochondrial dynamics, thus alleviating damage and cell dysfunction and enabling organelles to restore energy metabolism and maintain cell homeostasis [ 62 ]. At present, studies on the role and protective mechanism of mitophagy after ICH are relatively limited, and the effects of mitophagy and related targets are still controversial, such as Bcl-2/adenovirus E1B 19-kDa interacting proteins (BNIP3/BNIP3L) playing both positive and negative roles in different stroke disorders [ [63] , [64] , [65] ]. We will further explore the roles of the different targets in mitophagy and their functions under hypoxic conditions.…”

Traditional Chinese medicines treat ischemic stroke and their main bioactive constituents and mechanisms

“…Autophagy is a cellular mechanism that isolates damaged/aging organelles, excess proteins, and cellular components, thereby ensuring neuronal cell viability and overall CNS wellbeing by maintaining neuronal homeostasis, removing protein aggregates and damaged mitochondria, recycling amino acids, fatty acids, and glucose to maintain energy homeostasis, and reducing endoplasmic reticulum stress (ERS) (Li, Wu, et al, 2023). Mild-to-moderate induction of autophagy may act as a pro-survival mechanism in neuronal cells, a process often being referred to as adaptive autophagy.…”