{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:01:34Z","timestamp":1785402094664,"version":"3.56.0"},"posted":{"date-parts":[[2026,6,2]]},"group-title":"Cell Biology","reference-count":35,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T00:00:00Z","timestamp":1780358400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"award":["Intramural Research Program"],"award-info":[{"award-number":["Intramural Research Program"]}],"id":[{"id":"https:\/\/ror.org\/03wkg3b53","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Fundaci\u00f3n S\u00e9neca, Agencia de Ciencia y Tecnolog\u00eda Regi\u00f3n de Murcia","award":["22395\/SF\/23"],"award-info":[{"award-number":["22395\/SF\/23"]}]},{"DOI":"10.13039\/100000066","name":"National Institute of Environmental Health Sciences","doi-asserted-by":"crossref","award":["ZIC ES103363-01"],"award-info":[{"award-number":["ZIC ES103363-01"]}],"id":[{"id":"10.13039\/100000066","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Secondary degeneration following optic nerve crush (ONC) is driven in part by mitochondrial dysfunction and microglial activation. Inspired by hibernation, where reduced succinate oxidation limits reactive oxygen species (ROS) production, we tested whether pharmacological inhibition of this pathway confers neuroprotection. Using\n                  <jats:italic>in vivo<\/jats:italic>\n                  ONC models and\n                  <jats:italic>in vitro<\/jats:italic>\n                  microglial assays, we evaluated the effects of dimethyl malonate (DMM), an inhibitor of succinate dehydrogenase, and a cell-permeable succinate analog (succinate-NV). Succinate-NV increased pro-inflammatory cytokine expression (IL-1\u03b2) and reduced anti-inflammatory IL-10, whereas non-permeable succinate had no effect, indicating that intracellular succinate can drive microglial activation. In hibernating animals, succinate-NV disrupted neuroprotection and reduced retinal ganglion cell (RGC) survival following optic nerve injury. Although DMM partially reduced select inflammatory cytokines, it failed to normalize IL-1\u03b2 or IL-10 and suppressed microglial phagocytosis while exhibiting cytotoxic effects. In vivo, DMM-treated animals showed reduced IBA1\u25a1 microglia but increased CD68\u25a1 activation and accumulation of DAPI\u25a1 cells at 7 days post-injury at the crush site. RGC somas persisted but were Caspase3+ consistent with impaired clearance. Astrocyte reactivity increased at lesion borders, while reduced and fragmented GFAP at the lesion site indicated localized astrocyte loss. Collectively, these findings demonstrate that inhibition of succinate oxidation alone is insufficient for neuroprotection and underscore the need for coordinated metabolic and immune regulation that cannot be achieved through single-pathway pharmacological intervention.\n                <\/jats:p>","DOI":"10.64898\/2026.05.29.724314","type":"posted-content","created":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T14:21:17Z","timestamp":1780410077000},"source":"Crossref","is-referenced-by-count":1,"title":["Metabolic Intervention with Dimethyl Malonate Impairs Phagocytic Clearance but Fails to Protect Neurons"],"prefix":"10.64898","author":[{"given":"Rachel","family":"McNeel","sequence":"first","affiliation":[{"name":"National Eye Institute, NIH, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco M.","family":"Nadal-Nicol\u00e1s","sequence":"additional","affiliation":[{"name":"National Eye Institute, NIH, Bethesda, MD, USA"},{"name":"Department of Ophthalmology, Faculty of Medicine, University of Murcia and Biomedical Research Institute of Murcia (IMIB-Pascual Parrilla), Murcia 30120, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirsten","family":"Overdahl","sequence":"additional","affiliation":[{"name":"Metabolomics Core Facility, National Institute of Environmental Health Sciences, NIH, Durahm, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Li","sequence":"additional","affiliation":[{"name":"National Eye Institute, NIH, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan","family":"Jarmusch","sequence":"additional","affiliation":[{"name":"Metabolomics Core Facility, National Institute of Environmental Health Sciences, NIH, Durahm, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9744-3152","authenticated-orcid":false,"given":"Kiyoharu J.","family":"Miyagishima","sequence":"additional","affiliation":[{"name":"National Eye Institute, NIH, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026060511203338000_2026.05.29.724314v1.1","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.08-3267"},{"issue":"1","key":"2026060511203338000_2026.05.29.724314v1.2","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1186\/s12974-017-0982-7","article-title":"Microglial dynamics after axotomy-induced retinal ganglion cell death","volume":"14","year":"2017","journal-title":"J Neuroinflammation"},{"issue":"15","key":"2026060511203338000_2026.05.29.724314v1.3","doi-asserted-by":"crossref","first-page":"6073","DOI":"10.7150\/ijbs.102551","article-title":"Annexin-V binds subpopulation of immune cells altering its interpretation as an in vivo biomarker for apoptosis in the retina","volume":"20","year":"2024","journal-title":"Int J Biol Sci"},{"key":"2026060511203338000_2026.05.29.724314v1.4","unstructured":"Li W , Zhao T , Ou J , Nadal-Nicolas F , Ball J. Microglia suppression during hibernation prevents axonal injury-induced retinal ganglion cell death in the ground squirrel retina. Association for Research in Vision and Ophthalmology (ARVO); Honolulu, HI: Investigative Ophthalmology & Visual Science; 2018."},{"issue":"1","key":"2026060511203338000_2026.05.29.724314v1.5","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1186\/s12974-017-0982-7","article-title":"Microglial dynamics after axotomy-induced retinal ganglion cell death","volume":"14","year":"2017","journal-title":"J Neuroinflammation"},{"key":"2026060511203338000_2026.05.29.724314v1.6","unstructured":"Miyagishima KJ , Li W , Stasheff SF , Nadal-Nicolas FM . Targeted treatment of traumatic optic neuropathy inspired by neuroprotective adaptations of hibernation. Command USAMRaD; 2021. 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