NAD+-Boosters Improve Mitochondria Quality Control In Parkinson's Disease Models Via Mitochondrial UPR

Area of Science:

• Cellular Biology
• Neuroscience
• Biochemistry

Background:

• Mitochondrial dysfunction is central to Parkinson's disease (PD) pathogenesis.
• Mitochondrial quality control (MQC) mechanisms are critical for cellular health.
• The therapeutic potential of targeting MQC in PD remains largely unexplored.

Purpose of the Study:

• To investigate the role of NAD+ levels in MQC and PD.
• To determine if NAD+ boosting can serve as a therapeutic strategy for PD.

Main Methods:

• Utilized clinical samples, molecular biology, pharmacological interventions, and genetic models.
• Administered NAD+ boosters (NMN, siCD38, NAT) to rotenone-treated cells and MPTP-induced PD mice.
• Performed omics signatures and metabolomic profiling of the striatum.

Main Results:

• NAD+ boosters enhanced UPR^mt/mitophagy-related MQC, reduced inflammation, and inhibited apoptosis in cellular models.
• NMN supplementation ameliorated motor deficits and neuropathological signs in PD mice.
• NMN induced transcriptional changes related to mitochondrial homeostasis in the striatum.

Conclusions:

• Impaired MQC likely mediates accelerated pathology in PD models.
• Enhancing cellular NAD+ levels can alleviate mitochondrial proteotoxic stress.
• Boosting NAD+ is a promising therapeutic approach to mitigate PD phenotypes.