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Updated: Mar 15, 2026

The Use of Primary Human Fibroblasts for Monitoring Mitochondrial Phenotypes in the Field of Parkinson's Disease
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Nuclear factor erythroid 2-related factor 2 induction abrogates mitochondrial stress through parkin regulation

Narukkottil Safreena1, Jimna Mohamed Ameer2, Indu C Nair3

  • 1Cell Biology Laboratory, Centre for Development and Aging Research, Inter University Centre for Biomedical Research & Super Speciality Hospital, Mahatma Gandhi University Campus at Thalappady, Rubber Board PO, Kottayam, 686009, Kerala, India; School of Health Sciences, Purdue University, West Lafayette, IN, 47907, USA.

Free Radical Biology & Medicine
|March 13, 2026
PubMed

Insights

Mitochondrial stress causes Parkinson

Area of Science:

  • Neuroscience
  • Cell Biology
  • Biochemistry

Background:

  • Mitochondrial stress (MS) is a key feature of aging-associated neurodegenerative diseases like Parkinson's disease (PD).
  • Chronic MS disrupts neuronal proteostasis and leads to dopaminergic neurodegeneration.
  • The precise mechanism by which MS inactivates the E3 ubiquitin ligase parkin remains unclear.

Purpose of the Study:

  • To elucidate the mechanistic framework linking progressive changes in mitochondrial mass to MS-induced alterations in parkin activity.
  • To investigate the role of the parkin-PARIS-PGC1α pathway in response to acute and chronic mitochondrial stress.
  • To evaluate the therapeutic potential of methylene blue (MB) in mitigating mitochondrial and proteostatic failure in PD.

Main Methods:

  • Investigated the differential modulation of parkin activity by acute and chronic MS.
  • Analyzed the transcriptional control of peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) via the parkin substrate PARIS.
  • Assessed the effects of methylene blue (MB) on the NRF2-parkin axis and mitochondrial function in cells exposed to the PD neurotoxin MPP+.

Main Results:

  • Acute MS activates the parkin-PARIS-PGC1α pathway, transiently boosting mitochondrial biogenesis.
  • Chronic MS leads to parkin inactivation, PARIS accumulation, PGC1α repression, and loss of mitochondrial mass.
  • MB treatment restores parkin activity, reduces PARIS levels, reactivates PGC1α, and rejuvenates mitochondria by targeting the NRF2-parkin axis.

Conclusions:

  • Chronic mitochondrial damage significantly impairs parkin function in Parkinson's disease.
  • The NRF2-parkin axis is a critical target for therapeutic intervention in PD.
  • Methylene blue shows promise in protecting against mitochondrial and proteostatic failure in PD.
Keywords:
Dopaminergic neurodegenerationE3 ubiquitin ligaseMitochondriaParkinProteostasis

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