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Early bioenergetic collapse\u2014driven by mitochondrial depolarization, Reactive oxygen species (ROS) overproduction, and impaired mitophagy\u2014initiates 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\u2014including mitophagy modulation, Dynamin-related protein 1 (Drp1) inhibition, antioxidant nanocarriers, and emerging mitochondrial transplantation\u2014restore 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, \u03b1-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-1\u03b2 (IL-1\u03b2), Tumor necrosis factor-\u03b1 (TNF-\u03b1), 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\u2013mediated 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\u2014combining mitochondrial repair, synaptic stabilization, and immunomodulation\u2014along 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\u2013synapse\u2013inflammation 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.<\/jats:p>","DOI":"10.31083\/fbl49412","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T12:35:31Z","timestamp":1788438931000},"source":"Crossref","is-referenced-by-count":0,"title":["Reversible vs. Irreversible Neuronal Injury in Brain Ischemia: Role of the Mitochondrial\u2013Synaptic Axis"],"prefix":"10.31083","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0575-275X","authenticated-orcid":true,"given":"Ki-Yeon","family":"Yoo","sequence":"first","affiliation":[{"name":"Department of Anatomy, College of Dentistry and Research Institute for Dental Engineering, Kangwon National University, 25457 Gangneung, Gangwon, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2283-6066","authenticated-orcid":true,"given":"Bo Hyun","family":"Jung","sequence":"additional","affiliation":[{"name":"Department of Anatomy, College of Dentistry and Research Institute for Dental Engineering, Kangwon National University, 25457 Gangneung, Gangwon, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5304-0714","authenticated-orcid":true,"given":"Ji Hyeon","family":"Ahn","sequence":"additional","affiliation":[{"name":"Department of Physical Therapy, College of Health Science, Youngsan University, 50510 Yangsan, Gyeongsangnam-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7178-6501","authenticated-orcid":true,"given":"Moo-Ho","family":"Won","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, School of Medicine, Kangwon National University, 24341 Chuncheon, Gangwon, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2026,8,18]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Chamorro \u00c1, Dirnagl U, Urra X, Planas AM. 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