2. Academic Validation
  3. PKM2 alleviates mitochondrial oxidative stress and neuronal apoptosis through metabolic and non-metabolic pathways to protect SOD1G93A mice

PKM2 alleviates mitochondrial oxidative stress and neuronal apoptosis through metabolic and non-metabolic pathways to protect SOD1G93A mice

  • Free Radic Biol Med. 2025 Jun 15:238:1-16. doi: 10.1016/j.freeradbiomed.2025.06.012.
Zhuo Zhang 1,  Xia Guo 2,  Yan Liu 3,  Pingyang Ke 3,  Yuan Meng 3,  Juan Gu 4,  Liqin Hu 3,  Ziwei Yuan 3,  Ran Duan 3,  Jing Luo 5,  Fei Xiao 6
Affiliations

Affiliations

  • 1 Department of Neurology, Chongqing Key Laboratory of Major Neurological and Mental Disorders, Neurology Key Laboratory of Chongqing Education Commission of China, Chongqing Key Laboratory of Neurology, The First Affiliated Hospital of Chongqing Medical University, No.1 Youyi Road, Yuzhong District, Chongqing, 400016, China; Department of Rare Disease, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China; Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education), Chongqing Medical University, Chongqing, 400016, China.
  • 2 Department of Neurology, The Second Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, 563000, China.
  • 3 Department of Neurology, Chongqing Key Laboratory of Major Neurological and Mental Disorders, Neurology Key Laboratory of Chongqing Education Commission of China, Chongqing Key Laboratory of Neurology, The First Affiliated Hospital of Chongqing Medical University, No.1 Youyi Road, Yuzhong District, Chongqing, 400016, China.
  • 4 Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, 646000, China.
  • 5 Department of Neurology, Chongqing Key Laboratory of Major Neurological and Mental Disorders, Neurology Key Laboratory of Chongqing Education Commission of China, Chongqing Key Laboratory of Neurology, The First Affiliated Hospital of Chongqing Medical University, No.1 Youyi Road, Yuzhong District, Chongqing, 400016, China; Department of Rare Disease, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China; Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education), Chongqing Medical University, Chongqing, 400016, China. Electronic address: jgire@163.com.
  • 6 Department of Neurology, Chongqing Key Laboratory of Major Neurological and Mental Disorders, Neurology Key Laboratory of Chongqing Education Commission of China, Chongqing Key Laboratory of Neurology, The First Affiliated Hospital of Chongqing Medical University, No.1 Youyi Road, Yuzhong District, Chongqing, 400016, China; Department of Rare Disease, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China; Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education), Chongqing Medical University, Chongqing, 400016, China. Electronic address: feixiao81@126.com.
PMID: 40527446 DOI: 10.1016/j.freeradbiomed.2025.06.012
Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by selective motor neuron death. Dysregulated energy metabolism is implicated in ALS pathogenesis, yet the role of Pyruvate Kinase M2 (PKM2), a key glycolytic enzyme, remains elusive. Here, we demonstrated that PKM2 expression was upregulated in the spinal neurons of SOD1G93A mice during early stages of disease. Pharmacological inhibition of PKM2 with compound 3k (C3k) shortened survival times, exacerbated motor deficits, and amplified mitochondrial oxidative stress and neuronal Apoptosis in mice with ALS. Mechanistically, PKM2 mitigated mitochondrial dysfunction via its enzymatic activity, promoting lactate metabolism to reduce Reactive Oxygen Species (ROS) accumulation. Concurrently, nuclear PKM2 directly bound to the Nrf2 promoter, enhancing Nrf2 transcription to strengthen antioxidant defenses. Our findings unveil PKM2 as a multifunctional neuroprotectant in ALS, offering novel therapeutic directions through metabolic and transcriptional modulation.

Keywords

ALS; Apoptosis; Nrf2; Oxidative stress; PKM2.

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