Microglial Autophagy and Mitophagy in Ischemic Stroke: From Dual Roles to Therapeutic Modulation

Abstract

Ischemic stroke induces complex neuroinflammatory cascades, where microglial autophagy and mitophagy serve dual roles in both injury amplification and tissue repair. This scoping review synthesized current evidence on their regulatory mechanisms and therapeutic implications. Literature was identified via PubMed and Embase, yielding 79 records, from which 39 original research articles and 13 review papers were included after eligibility screening. Search terms included "microglia," "autophagy," and "ischemic stroke." Protective autophagy was frequently associated with AMPK activation, mTOR inhibition, and mitophagy pathways such as PINK1/Parkin and BNIP3/NIX, facilitating mitochondrial clearance, M2 polarization, and anti-inflammatory signaling. Therapeutic agents such as rapamycin, Tat-Beclin 1, and Urolithin A consistently demonstrated neuroprotection in preclinical stroke models. In contrast, excessive or prolonged autophagic activation was linked to inflammasome amplification, oxidative stress, and phagoptosis. Limited human studies reported associations between elevated serum ATG5 levels or ATG7 polymorphisms and worse clinical outcomes, suggesting preliminary translational relevance. These findings support the potential of phase-specific modulation of microglial autophagy as a therapeutic avenue for stroke, although further validation in human models and development of autophagy biomarkers are needed for clinical application.

Keywords: M1/M2 polarization; PINK1/Parkin; autophagy; inflammasome; ischemic stroke; microglia; mitophagy; neuroinflammation.

Figure 1

PRISMA flow diagram illustrating the study selection process.

Figure 2

Protective regulatory networks of microglial autophagy following ischemic stroke. After cerebral ischemia, ATP depletion and DAMP release trigger microglial activation and polarization. This figure summarizes the molecular signaling pathways that promote autophagy-mediated neuroprotection in microglia. Stress signals activate the AMPK–ULK1–Beclin1 complex and inhibit mTOR, thereby inducing autophagy. ER stress–mediated IRE1/JNK and HIF-1α–BNIP3 pathways also contribute to autophagy and mitophagy. Key upstream regulators such as α7nAChR and PARP14 modulate inflammatory states and enhance autophagic flux. Non-coding RNAs—including MALAT1, miR-26b, and miR-499-5p—participate in ceRNA networks that facilitate ULK2 and ATG5 expression. Pharmacological agents such as α-asarone promote protective autophagy by targeting these axes. Through mitochondrial quality control, inflammasome suppression, and phenotypic transition from M1 to M2, autophagy acts as a critical mediator of microglial homeostasis in the early phase post-stroke. In this figure, green arrows indicate activation/promotion, blue arrows indicate inhibition, red arrows indicate increased expression, and black arrows indicate reduced expression.

Figure 3

Pathological signaling pathways underlying dysregulated microglial autophagy after ischemic stroke. Following cerebral ischemia, ATP depletion and ROS overproduction lead to mitochondrial dysfunction and the release of DAMPs and mtDNA, which trigger innate immune responses in microglia. This figure summarizes the molecular mechanisms by which sustained or excessive autophagy contributes to neuroinflammation and neuronal injury. Activation of TLR9 and the cGAS–STING axis promotes NF-κB–mediated expression of IL-1β, IL-6, and TNF-α. Mitochondrial Ca²⁺ overload and ER stress exacerbate autophagic activity via Beclin1–PI3K complexes, while persistent p62 accumulation amplifies NLRP3 inflammasome activation. Disruption of CX3CL1–CX3CR1 signaling impairs neuron–microglia communication and further skews microglia toward an M1-like pro-inflammatory phenotype. Additionally, miR-30d suppresses CX3CL1 expression, contributing to inflammatory amplification and apoptotic signaling. These maladaptive pathways form a positive feedback loop linking defective autophagic resolution, mitochondrial DAMP signaling, and chronic neuroinflammation in ischemic stroke. In this figure, green arrows indicate activation/promotion, blue arrows indicate inhibition, black arrows represent downregulation or suppression, red arrows indicate upregulation or enhancement, and purple arrows represent inflammatory signaling pathways.

Figure 4

Molecular mechanisms underlying microglial mitophagy in ischemic stroke and their immunometabolic implications. Upon ischemic injury, mitochondrial depolarization and ROS accumulation initiate selective mitophagy through two primary pathways: PINK1/Parkin and BNIP3/NIX. In the PINK1/Parkin axis, damaged mitochondria accumulate ubiquitinated proteins on their outer membranes, which subsequently recruit autophagy receptors such as p62 to facilitate autophagosome formation. In parallel, BNIP3 and NIX act as mitophagy receptors by directly interacting with LC3 via their LC3-interacting region (LIR) motifs, thus mediating receptor-dependent mitophagy. Mitochondrial DNA (mtDNA) leakage from compromised organelles activates the cGAS–STING signaling cascade, which in turn stimulates the NLRP3 inflammasome, escalating neuroinflammation. Moderate levels of mitophagy counteract this process by promoting M1-to-M2 microglial polarization, thereby enhancing neuroprotection and axonal regeneration. Conversely, excessive or insufficient mitophagy exacerbates neuroinflammatory responses and contributes to neuronal cell death. This figure encapsulates the dual immunometabolic outcomes of mitophagy modulation in microglial responses to cerebral ischemia. In this figure, green arrows represent activation or promotion, blue arrows indicate inhibition, black arrows denote decreased activity or expression, red arrows reflect increased expression, and purple arrows indicate autophagy-related pathways.