Mitochondrial complex I deficiency stratifies idiopathic Parkinson's disease

Nat Commun. 2024 Apr 29;15(1):3631. doi: 10.1038/s41467-024-47867-4.


Idiopathic Parkinson's disease (iPD) is believed to have a heterogeneous pathophysiology, but molecular disease subtypes have not been identified. Here, we show that iPD can be stratified according to the severity of neuronal respiratory complex I (CI) deficiency, and identify two emerging disease subtypes with distinct molecular and clinical profiles. The CI deficient (CI-PD) subtype accounts for approximately a fourth of all cases, and is characterized by anatomically widespread neuronal CI deficiency, a distinct cell type-specific gene expression profile, increased load of neuronal mtDNA deletions, and a predilection for non-tremor dominant motor phenotypes. In contrast, the non-CI deficient (nCI-PD) subtype exhibits no evidence of mitochondrial impairment outside the dopaminergic substantia nigra and has a predilection for a tremor dominant phenotype. These findings constitute a step towards resolving the biological heterogeneity of iPD with implications for both mechanistic understanding and treatment strategies.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • DNA, Mitochondrial* / genetics
  • Electron Transport Complex I* / deficiency*
  • Electron Transport Complex I* / genetics
  • Electron Transport Complex I* / metabolism
  • Female
  • Humans
  • Male
  • Middle Aged
  • Mitochondria* / genetics
  • Mitochondria* / metabolism
  • Mitochondrial Diseases* / genetics
  • Mitochondrial Diseases* / metabolism
  • Neurons / metabolism
  • Parkinson Disease* / genetics
  • Parkinson Disease* / metabolism
  • Phenotype
  • Substantia Nigra / metabolism
  • Substantia Nigra / pathology


  • Electron Transport Complex I
  • DNA, Mitochondrial

Supplementary concepts

  • Mitochondrial complex I deficiency