Reversible vs. Irreversible Neuronal Injury in Brain Ischemia: Role of the Mitochondrial-Synaptic Axis.

Ischemia-reperfusion (I/R) injury triggers a rapid and self-amplifying cascade of mitochondrial dysfunction, synaptic instability, and neuroinflammation that ultimately determines neuronal survival and functional recovery. Early bioenergetic collapse-driven by mitochondrial depolarization, Reactive oxygen species (ROS) overproduction, and impaired mitophagy-initiates excitotoxic signaling and calpain-mediated structural degradation at vulnerable synapses. These events converge with microglial and astrocytic activation to exacerbate cytokine release, blood-brain barrier (BBB) disruption, and delayed neuronal injury. Therapeutic strategies targeting this axis show considerable promise. Mitochondria-directed interventions-including mitophagy modulation, Dynamin-related protein 1 (Drp1) inhibition, antioxidant nanocarriers, and emerging mitochondrial transplantation-restore Adenosine triphosphate (ATP) production, stabilize membrane potential, and prevent downstream excitotoxic injury. Synaptic protection via N-methyl-D-aspartate (NMDA)/postsynaptic density protein-95 (PSD-95) uncoupling, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor stabilization, and calpain inhibition preserves dendritic architecture and neurotransmission. Modulation of inflammatory pathways, particularly Interleukin-1β (IL-1β), Tumor necrosis factor-α (TNF-α), and Interleukin-6 (IL-6) signaling, as well as cell-specific microglial and astrocytic reprogramming, further attenuates secondary degeneration. Gene- and RNA-based therapies, nanoparticles engineered for BBB penetration, and extracellular vesicle-mediated delivery systems represent additional advanced platforms moving toward clinical translation. Despite substantial progress, challenges remain, including timing constraints, region-specific vulnerability (e.g., CA1 vs. CA3), limited BBB permeability, and species differences in mitochondrial dynamics and glial responses. Integrative multimodal strategies-combining mitochondrial repair, synaptic stabilization, and immunomodulation-along with advanced imaging, spatial transcriptomics, and patient-derived organoids, may accelerate the development of precision therapies for I/R injury. This review synthesizes mechanistic and translational evidence demonstrating that the mitochondria-synapse-inflammation axis forms a unified pathological framework across experimental and clinical I/R settings, including transient focal ischemia, global ischemia following cardiac arrest (CA), and reperfusion after thrombolysis or thrombectomy.