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GGGGCC repeat expansion in C9orf72 is the most common genetic cause of both ALS and FTD. A key pathological feature of C9orf72 related ALS\/FTD is the presence of abnormal dipeptide repeat proteins translated from GGGGCC repeat expansion, including poly Glycine\u2010Arginine (GR). In this study, we observed that (GR)<jats:sub>50<\/jats:sub> conferred significant mitochondria damage and cytotoxicity. Metformin, the most widely used clinical drug, successfully relieved (GR)<jats:sub>50<\/jats:sub> induced mitochondrial damage and inhibited (GR)<jats:sub>50<\/jats:sub> related cytotoxicity. Further research revealed metformin effectively restored mitochondrial function by upregulating AKT phosphorylation in (GR)<jats:sub>50<\/jats:sub> expressed cells. Taken together, our results indicated restoring mitochondrial function with metformin may be a rational therapeutic strategy to reduce poly(GR) toxicity in C9orf72 ALS\/FTD patients.<\/jats:p>","DOI":"10.1002\/jcb.30526","type":"journal-article","created":{"date-parts":[[2024,1,17]],"date-time":"2024-01-17T08:08:48Z","timestamp":1705478928000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Metformin ameliorates mitochondrial damage induced by C9orf72 poly(GR) via upregulating AKT phosphorylation"],"prefix":"10.1002","volume":"125","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8719-0879","authenticated-orcid":false,"given":"Yiyuan","family":"Feng","sequence":"first","affiliation":[{"name":"Department of Nuclear Medicine Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine Shanghai China"},{"name":"Department of Radiology Fujian Provincial Hospital Fuzhou Fujian 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