2. Academic Validation
  3. Homocysteine interferes with Ndufa1 leading to mitochondrial dysfunction through repression of the NAD+/Sirt1 pathway in the brain: a possible link between hyperhomocysteinemia and neurodegeneration

Homocysteine interferes with Ndufa1 leading to mitochondrial dysfunction through repression of the NAD+/Sirt1 pathway in the brain: a possible link between hyperhomocysteinemia and neurodegeneration

  • Cell Death Dis. 2025 Jul 7;16(1):499. doi: 10.1038/s41419-025-07834-3.
Gaoshang Chai # 1 2,  Yuming Mao # 3,  Juan Gong 3,  Shuguang Bi 3,  Yuqi Zhang 3,  Jiajun Wu 4,  Liu Yang 3,  Tianlong Gao 3,  Haitian Fu 5,  Chunjing Yu 5,  Caili Ren 6,  Guofu Zhang 7,  Xuming Zhu 8,  Xin Guan 9,  Haoting Yu 3,  Caijing Tang 3,  Yunjuan Nie 3,  Haitao Yu 10
Affiliations

Affiliations

  • 1 Department of Fundamental Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China. chaigaoshang@jiangnan.edu.cn.
  • 2 MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China. chaigaoshang@jiangnan.edu.cn.
  • 3 Department of Fundamental Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China.
  • 4 Department of Electrophysiology, Wuhan Children's Hospital (Wuhan Maternal and Children's Healthcare Center), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
  • 5 Nuclear Medicine Center, Jiangnan University Affiliated Hospital, Wuxi, Jiangsu, China.
  • 6 Department of Neurology, The Affiliated Mental Health Center of Jiangnan University, Wuxi, Jiangsu, China.
  • 7 Department of Clinical Psychiatry, The Affiliated Mental Health Center of Jiangnan University, Wuxi, Jiangsu, China.
  • 8 Department of Laboratory Medicine, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu, China.
  • 9 Science Center for Future Foods, Jiangnan University, Wuxi, Jiangsu, China.
  • 10 Department of Fundamental Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China. yu_haitao@jiangnan.edu.cn.
  • # Contributed equally.
PMID: 40624018 DOI: 10.1038/s41419-025-07834-3
Abstract

Mitochondrial defects are early pathological changes in neurodegenerative disease (ND). Homocysteine (Hcy) is an independent risk factor for ND. However, whether and how Hcy induces mitochondrial defects during the process of neurodegeneration is unclear. Here, we revealed that Hcy interfered with mitochondrial Oxidative Phosphorylation (OXPHOS) by inhibiting the mitochondrial electron transport chain (ETC) complex I, resulting in increased levels of Reactive Oxygen Species (ROS) in the hippocampus of rats. Specifically, Hcy suppressed Ndufa1 expression, which is essential for complex I assembly and activation, by interfering with its transcription factor Creb1. Moreover, we found that Hcy induced neurodegeneration-like pathological changes in mitochondria in the brain via the inhibition of the NAD+/SIRT1 pathway, including defects in mitochondrial morphology, mitochondrial biogenesis, and Mitophagy, ultimately leading to impairments in synapses and cognition, all of which were reversed by Ndufa1 upregulation. Thus, Ndufa1 is a key molecular switch of Hcy-induced mitochondrial damage, and appropriately targeting Ndufa1 or NAD+ replenishment may serve as a novel therapeutic strategy for Hcy-induced neurodegeneration and cognitive impairment.

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