Metformin alleviates lead-induced mitochondrial fragmentation via AMPK/Nrf2 activation in SH-SY5Y cells

• Published in: Redox biology Vol. 36; p. 101626
• Main Authors: Yang, Luoyao, Li, Xiaoyi, Jiang, Anli, Li, Xintong, Chang, Wei, Chen, Jun, Ye, Fang
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-09-2020; Elsevier
• Subjects: AMP-Activated Protein Kinases - genetics; AMP-Activated Protein Kinases - metabolism; Humans; Lead; Lead - toxicity; Metformin; Metformin - pharmacology; Mitochondria - metabolism; Mitochondrial fragmentation; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Nrf2; Oxidative Stress; Reactive Oxygen Species - metabolism; Research Paper; Lead; Oxidative stress; Metformin; Nrf2; Mitochondrial fragmentation
• ISSN: 2213-2317; 2213-2317
• DOI: 10.1016/j.redox.2020.101626

As a widely acknowledged environmental pollutant, lead (Pb) exhibits neurological toxicity primarily due to the vulnerability of neural system. It is suggested that Pb could perturb mitochondrial function, triggering the following disturbance of cellular homeostasis. Here, we focused on the role of mitochondrial dynamics in Pb-induced cell damage. Pb exposure enhanced mitochondrial fragmentation and elevated p-Drp1 (s616) level in a reactive oxygen species (ROS) dependent manner, leading to cell death and energy shortage. By applying metformin, an AMP-activated protein kinase (AMPK) activator, these impairments could be alleviated via activation of AMPK, validated by experiments of pharmacological inhibition of AMPK. Further investigation confirmed that nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor managing antioxidative function, and its downstream antioxidant detoxifying enzyme were activated by metformin, resulting in the inhibition of the Pb-caused oxidative stress. Moreover, Nrf2 mediated the protection of metformin against mitochondrial fragmentation induced by Pb exposure, while knockdown of Nrf2 abrogated the protective effect. Finally, the treatment of Mdivi-1, a mitochondrial fission inhibitor, reversed Pb-triggered cell death, revealing that excessive mitochondrial fission is detrimental. To conclude, metformin could ameliorate Pb-induced mitochondrial fragmentation via antioxidative effects originated from AMPK/Nrf2 pathway activation, promoting energy supply and cell survival.
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•Pb caused mitochondrial fragmentation in a ROS dependent manner.•Metformin alleviated Pb-induced mitochondrial fission via Nrf2 activation.•AMPK mediated metformin-induced Nrf2 activation.•Inhibition of mitochondrial fragmentation rescued Pb-induced cell death.