{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T07:25:01Z","timestamp":1787210701276,"version":"build-2736575974"},"reference-count":94,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:00:00Z","timestamp":1787184000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by progressive loss of motor neurons. In addition to neurodegeneration, ALS is increasingly recognised as a disorder associated with widespread metabolic dysfunction, including hypermetabolism, weight loss, and dyslipidaemia, all of which correlate with disease progression and survival. Astrocytes play a central role in maintaining metabolic homeostasis in the central nervous system by supporting neuronal energy demands, regulating glutamate levels, buffering oxidative stress, and maintaining lipid balance. Emerging evidence suggests that disruption of these supportive astrocytic functions may contribute directly to motor neuron vulnerability in ALS. In this mini-review, we discuss how alterations in astrocyte metabolism may impair astrocyte-neuron metabolic coupling in ALS. We summarise work from human studies and experimental models demonstrating abnormalities in astrocytic glycolysis, mitochondrial function, lactate shuttling, lipid metabolism, and glutamate homeostasis. We highlight growing evidence implicating mitochondrial dysfunction and impaired lipid handling in astrocytes as important contributors to disease progression. We explore how these changes may deprive motor neurons of metabolic and antioxidant support while also promoting excitotoxicity, oxidative stress, and lipotoxicity. We also discuss how recent advances in human induced pluripotent stem cell models, metabolomics, and single-cell transcriptomics are improving our understanding of astrocyte dysfunction in ALS. Finally, we consider current and emerging therapeutic strategies aimed at restoring astrocytic metabolic function. Together, these findings support the idea that progressive failure of astrocyte-mediated metabolic support is an important component of ALS pathogenesis and may represent a promising therapeutic target.<\/jats:p>","DOI":"10.3389\/fcell.2026.1899307","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T07:02:45Z","timestamp":1787209365000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Disrupted astrocyte-neuron metabolic coupling in amyotrophic lateral sclerosis"],"prefix":"10.3389","volume":"14","author":[{"given":"\u00c1ine Br\u00edd","family":"Heffernan","sequence":"first","affiliation":[{"name":"UK Dementia Research Institute at University of Edinburgh, University of Edinburgh","place":["Edinburgh, United Kingdom"]},{"name":"Institute for Neuroscience and Cardiovascular Research, University of Edinburgh","place":["Edinburgh, United Kingdom"]},{"name":"Euan MacDonald Centre for MND Research, University of Edinburgh","place":["Edinburgh, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florence","family":"Do","sequence":"additional","affiliation":[{"name":"Edinburgh Medical School, The University of Edinburgh","place":["Edinburgh, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleanor","family":"Carter","sequence":"additional","affiliation":[{"name":"Edinburgh Medical School, The University of Edinburgh","place":["Edinburgh, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farah","family":"Al-Tameemi","sequence":"additional","affiliation":[{"name":"Edinburgh Medical School, The University of Edinburgh","place":["Edinburgh, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bhuvaneish T.","family":"Selvaraj","sequence":"additional","affiliation":[{"name":"UK Dementia Research Institute at University of Edinburgh, University of Edinburgh","place":["Edinburgh, United Kingdom"]},{"name":"Institute for Neuroscience and Cardiovascular Research, University of Edinburgh","place":["Edinburgh, United Kingdom"]},{"name":"Euan MacDonald Centre for MND Research, University of Edinburgh","place":["Edinburgh, United Kingdom"]},{"name":"Anne Rowling Regenerative Neurology Clinic, University of Edinburgh","place":["Edinburgh, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Stavrou","sequence":"additional","affiliation":[{"name":"UK Dementia Research Institute at University of Edinburgh, University of Edinburgh","place":["Edinburgh, United Kingdom"]},{"name":"Institute for Neuroscience and Cardiovascular Research, University of Edinburgh","place":["Edinburgh, United Kingdom"]},{"name":"Euan MacDonald Centre for MND Research, University of Edinburgh","place":["Edinburgh, United Kingdom"]},{"name":"Anne Rowling Regenerative Neurology Clinic, University of Edinburgh","place":["Edinburgh, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"3771","DOI":"10.1093\/brain\/awz302","article-title":"C9orf72 expansion within astrocytes reduces metabolic flexibility in amyotrophic lateral sclerosis","volume":"142","author":"Allen","year":"2019","journal-title":"Brain"},{"key":"B2","doi-asserted-by":"publisher","first-page":"212","DOI":"10.3389\/fncel.2019.00212","article-title":"Lipid metabolism crosstalk in the brain: glia and neurons","volume":"13","author":"Barber","year":"2019","journal-title":"Front. 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