Mitochondrial complex I deficiency occurs in skeletal muscle of a subgroup of individuals with Parkinson’s disease.

Apr 28, 2025

Experts: Simon Ulvenes Kverneng,Kjersti Eline Stige,Haakon Berven,Sepideh Mostafavi,Katarina Lundervold,Michele Brischigliaro,Brage Brakedal,Geir Olve Skeie,Irene Hana Flønes,Lilah Toker,Erika Fernandez-Vizarra,Ragnhild Eide Skogseth,Kristoffer Haugarvoll,Yamila N Torres Cleuren,Christian Dölle,Gonzalo S Nido,Charalampos Tzoulis

Widespread neuronal mitochondrial complex I (CI) deficiency was recently reported to be a characteristic in a subgroup of individuals with idiopathic Parkinson’s disease (PD). Here, we sought to determine whether a CI-deficient subgroup could be discerned using clinically accessible muscle biopsies. We further hypothesized that the inconsistency of previous findings of mitochondrial respiratory impairment in PD muscle may be due to interindividual variation, with respiratory deficiency only occurring in a subgroup of cases.
Using a cross-sectional design, vastus lateralis needle biopsies were collected from 83 individuals with PD and 29 neurologically healthy controls and analyzed by immunohistochemistry for CI and complex IV (CIV), cytochrome c oxidase/succinate dehydrogenase (COX/SDH) histochemistry, and spectrophotometric activity assays of complexes I-IV. Mitochondrial DNA (mtDNA) copy number, deletions, and point variation were analyzed in single muscle fibers and bulk biopsy samples.
We show that PD muscle exhibits reduced CI activity at the group level, with 9% of cases falling below two standard deviations of the control group. In contrast, the activities of CII-CIV are not significantly different between the PD and control groups. No quantitative change of CI or CIV is detected, and the observed functional CI deficiency is not associated with mtDNA abnormalities.
Our findings support the existence of a PD subpopulation characterized by CI pathology in skeletal muscle and suggest that stratification by extra-neural mitochondrial dysfunction may be informative for selecting individuals for clinical trials.

© 2025. The Author(s).

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ABOUT THE EXPERTS

Simon Ulvenes Kverneng,Kjersti Eline Stige,Haakon Berven,Sepideh Mostafavi,Katarina Lundervold,Michele Brischigliaro,Brage Brakedal,Geir Olve Skeie,Irene Hana Flønes,Lilah Toker,Erika Fernandez-Vizarra,Ragnhild Eide Skogseth,Kristoffer Haugarvoll,Yamila N Torres Cleuren,Christian Dölle,Gonzalo S Nido,Charalampos Tzoulis

Simon Ulvenes Kverneng

Neuro-SysMed, Department of Neurology, Haukeland University Hospital, Bergen, Norway.

Department of Clinical Medicine, University of Bergen, Bergen, Norway.

K.G. Jebsen Center for Translational Research in Parkinson’s Disease, University of Bergen, Bergen, Norway.

Kjersti Eline Stige

Neuro-SysMed, Department of Neurology, Haukeland University Hospital, Bergen, Norway.

Department of Clinical Medicine, University of Bergen, Bergen, Norway.

K.G. Jebsen Center for Translational Research in Parkinson’s Disease, University of Bergen, Bergen, Norway.

The Department of Neuromedicine and Movement Sciences (INB), Norwegian University of Science and Technology (NTNU), Trondheim, Norway.

Department of Neurology and Clinical Neurophysiology, St Olav’s University Hospital, Trondheim, Norway.

Haakon Berven

Neuro-SysMed, Department of Neurology, Haukeland University Hospital, Bergen, Norway.

Department of Clinical Medicine, University of Bergen, Bergen, Norway.

K.G. Jebsen Center for Translational Research in Parkinson’s Disease, University of Bergen, Bergen, Norway.

Sepideh Mostafavi

Neuro-SysMed, Department of Neurology, Haukeland University Hospital, Bergen, Norway.

Department of Clinical Medicine, University of Bergen, Bergen, Norway.

K.G. Jebsen Center for Translational Research in Parkinson’s Disease, University of Bergen, Bergen, Norway.

Katarina Lundervold

Neuro-SysMed, Department of Neurology, Haukeland University Hospital, Bergen, Norway.

Department of Clinical Medicine, University of Bergen, Bergen, Norway.

K.G. Jebsen Center for Translational Research in Parkinson’s Disease, University of Bergen, Bergen, Norway.

Michele Brischigliaro

Department of Biomedical Sciences, University of Padova, Padova, Italy.

Veneto Institute of Molecular Medicine, Padova, Italy.

Brage Brakedal

Neuro-SysMed, Department of Neurology, Haukeland University Hospital, Bergen, Norway.

Department of Clinical Medicine, University of Bergen, Bergen, Norway.

K.G. Jebsen Center for Translational Research in Parkinson’s Disease, University of Bergen, Bergen, Norway.

Geir Olve Skeie

Neuro-SysMed, Department of Neurology, Haukeland University Hospital, Bergen, Norway.

Department of Clinical Medicine, University of Bergen, Bergen, Norway.

K.G. Jebsen Center for Translational Research in Parkinson’s Disease, University of Bergen, Bergen, Norway.

Irene Hana Flønes

Neuro-SysMed, Department of Neurology, Haukeland University Hospital, Bergen, Norway.

Department of Clinical Medicine, University of Bergen, Bergen, Norway.

K.G. Jebsen Center for Translational Research in Parkinson’s Disease, University of Bergen, Bergen, Norway.

Lilah Toker

Neuro-SysMed, Department of Neurology, Haukeland University Hospital, Bergen, Norway.

Department of Clinical Medicine, University of Bergen, Bergen, Norway.

K.G. Jebsen Center for Translational Research in Parkinson’s Disease, University of Bergen, Bergen, Norway.

Erika Fernandez-Vizarra

Department of Biomedical Sciences, University of Padova, Padova, Italy.

Veneto Institute of Molecular Medicine, Padova, Italy.

Ragnhild Eide Skogseth

Department of Geriatric Medicine, Haraldsplass Deaconess Hospital, Bergen, Norway.

Department of Clinical Sciences, Faculty of Medicine, University of Bergen, Bergen, Norway.

Kristoffer Haugarvoll

Neuro-SysMed, Department of Neurology, Haukeland University Hospital, Bergen, Norway.

Department of Clinical Medicine, University of Bergen, Bergen, Norway.

K.G. Jebsen Center for Translational Research in Parkinson’s Disease, University of Bergen, Bergen, Norway.

Yamila N Torres Cleuren

Neuro-SysMed, Department of Neurology, Haukeland University Hospital, Bergen, Norway.

Department of Clinical Medicine, University of Bergen, Bergen, Norway.

K.G. Jebsen Center for Translational Research in Parkinson’s Disease, University of Bergen, Bergen, Norway.

Christian Dölle

Neuro-SysMed, Department of Neurology, Haukeland University Hospital, Bergen, Norway.

Department of Clinical Medicine, University of Bergen, Bergen, Norway.

K.G. Jebsen Center for Translational Research in Parkinson’s Disease, University of Bergen, Bergen, Norway.

Gonzalo S Nido

Neuro-SysMed, Department of Neurology, Haukeland University Hospital, Bergen, Norway.

Department of Clinical Medicine, University of Bergen, Bergen, Norway.

K.G. Jebsen Center for Translational Research in Parkinson’s Disease, University of Bergen, Bergen, Norway.

Charalampos Tzoulis

Neuro-SysMed, Department of Neurology, Haukeland University Hospital, Bergen, Norway. charalampos.tzoulis@uib.no.

Department of Clinical Medicine, University of Bergen, Bergen, Norway. charalampos.tzoulis@uib.no.

K.G. Jebsen Center for Translational Research in Parkinson’s Disease, University of Bergen, Bergen, Norway. charalampos.tzoulis@uib.no.