2. Academic Validation
  3. Metformin ameliorates mitochondrial damage induced by C9orf72 poly(GR) via upregulating AKT phosphorylation

Metformin ameliorates mitochondrial damage induced by C9orf72 poly(GR) via upregulating AKT phosphorylation

  • J Cell Biochem. 2024 Jan 17. doi: 10.1002/jcb.30526.
Yiyuan Feng 1 2,  Zhongyun Xu 1 3,  Hongfu Jin 1,  Yuanyuan Chen 4,  Chenglai Fu 4,  Yu Zhang 5,  Yafu Yin 1,  Hui Wang 1,  Weiwei Cheng 1
Affiliations

Affiliations

  • 1 Department of Nuclear Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2 Department of Radiology, Fujian Provincial Hospital, Fuzhou, Fujian, China.
  • 3 Department of Radiology, Shanghai East Hospital Affiliated to Tongji University, Shanghai, China.
  • 4 Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 5 Department of Neurology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
PMID: 38229533 DOI: 10.1002/jcb.30526
Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative diseases with no effective cure. 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-Arginine (GR). In this study, we observed that (GR)50 conferred significant mitochondria damage and cytotoxicity. Metformin, the most widely used clinical drug, successfully relieved (GR)50 induced mitochondrial damage and inhibited (GR)50 related cytotoxicity. Further research revealed metformin effectively restored mitochondrial function by upregulating Akt phosphorylation in (GR)50 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.

Keywords

AKT; C9ALS/FTD; metformin; mitochondria; poly GR.

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