Multi-omics analysis of hypoxia-mitochondrial energy metabolism and programmed cell death profiling in Parkinson’s disease

Hypoxia and mitochondrial energy metabolism (MEM) impairment are pivotal features of Parkinson’s disease (PD), yet the regulators linking hypoxic stress to mitochondrial failure remain elusive. Here we integrated multiple transcriptomic datasets from the substantia nigra to characterize the hypoxia and MEM landscape. Utilizing a tripartite machine learning framework combined with LASSO-logistic regression, we developed a robust seven-gene diagnostic model that achieved high predictive accuracy (AUC: 0.887 training; 0.821 validation).

Two-sample Mendelian randomization (MR) analysis further identified seven causal genes (TTC19, SERPINA1, MPC2, DLK1, DDIT4, AUH, and ASL) associated with PD risk. By integrating programmed cell death (PCD) profiling and scRNA-seq, we discovered that core regulators MPC2 and AUH were uniquely associated with novel PCD modes, showing negative correlations with alkaliptosis and positive correlations with cuproptosis. Single-cell analysis localized primary hypoxia-MEM impairment to dopaminergic neurons (DaNs), where MPC2 expression was significantly depleted.

In silico virtual knockout of MPC2 disrupted dopamine metabolism and synaptic vesicle cycles, while STAT3 and MEF2A were identified as potential upstream transcription factors linking metabolic dysfunction to neuroinflammation. Together, our findings identify MPC2 as a genetically supported causal regulator linking hypoxia-MEM failure to novel PCD in DaNs, offering potential biomarkers and therapeutic targets for precision intervention in PD. This work was supported by grants from the National Natural Science Foundation of China (No. 8237053046).

These authors contributed equally: An Chang, Yi Wu. Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China An Chang, Zhuoran Ma, Zhicheng Tang, Haoxuan Ouyang, Maoyu Liu, Xuebing Cao, Heng Zhai & Yan Xu Department of Neurology, The Affiliated Hospital of Southwest Jiaotong University & The Third People’s Hospital of Chengdu, Chengdu, China Department of Neurology and National Center for Neurological Disorders, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China The authors declare no competing interests. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Chang, A., Wu, Y., Lian, P. et al. Multi-omics analysis of hypoxia-mitochondrial energy metabolism and programmed cell death profiling in Parkinson’s disease. npj Parkinsons Dis. (2026). https://doi.org/10.1038/s41531-026-01576-5 DOI: https://doi.org/10.1038/s41531-026-01576-5