While the clinical trial in the article does not target PD, some interesting facts that may be related to PD. (Inflammation).
Will leave to you guys to infer, especially something related Parkin-mediated Mitophagy and how it is affected in PD patients
cell.com/cell-reports-medic...
Below are excerpt From the Article : Note the mention of 'Urolithin A (UA) activates PINK1/Parkin-mediated mitophagy in the human skeletal muscle.'
C-reactive protein (CRP) is a well-established plasma biomarker of inflammation linked to aging34,35and high BMI.36
As expected, middle-aged overweight ATLAS participants showed high average plasma CRP concentrations (approximately 3 mg/L; Figure S3B), which is associated with moderate to high risk of age-related chronic diseases.34,35
Administration of UA reduced plasma CRP levels at both doses, with results statistically significant at the 1,000 mg dose (Figure 3C). UA also led to an overall reduction of some pro-inflammatory cytokines, such as interferon gamma (IFN-γ), interleukin-1 beta (IL-1β), and tumor necrosis factor alpha (TNF-α) (Figure 3D). Average baseline levels of these pro-inflammatory cytokines were low in this population. For several subjects, IL-1β values were below the limit of detection. Despite this limitation, combined data from both CRP and inflammatory cytokines suggest a mild anti-inflammatory effect of UA at the systemic level. Altogether, these results indicate that UA-mediated improvement of muscle function associates with both enhanced mitochondrial efficiency and reduced inflammation.
In the proteomic analysis, the most significantly enriched pathway induced in the UA 500 mg group was “Parkin-mediated ubiquitin and proteasomal systems” (Figures 5B and S5C). This pathway contains ubiquitin-conjugating enzymes (UBEs) and proteasomal components (PSMs) (Figure S5D; Table S2), which are required for Parkin-mediated degradation of dysfunctional mitochondria and damaged proteins. Enzymes such as UBE2N and UBE2R2 were previously shown to be essential for PINK1/Parkin-mediated mitophagy.41,42
A trend toward the increase in these mitophagy-related proteins was observed also at the 1,000 mg dose (Figure S5D). Protein levels of the PINK1/Parkin-independent mitophagy regulator BNIP3 decreased in the 1,000 mg cohort (Figure S5E; Table S2), indicating a specific effect of UA on the PINK1/Parkin-mediated mitophagy axis. Top pathways enriched at the 1,000 mg dose were associated with improved mitochondrial metabolism (Figures 5C and S6A) and included proteins related to the mitochondrial tricarboxylic acid (TCA) cycle, fatty-acid oxidation, electron transport chain (ECT), and oxidative phosphorylation (OXPHOS) (Figure S6B; Table S2). Several of these mitochondrial proteins were upregulated by UA in a dose-dependent manner (Figure S6C). Among proteins indicative of mitochondria content, TOMM20 increased in the UA 1,000 mg group, although not significantly, while VDAC levels remained unchanged in all cohorts (Figure S6C; Table S2). No change was observed for proteins related to mitochondrial remodeling, such as MFN1, MFN2, DRP1, and OPA1 (Figure S6C; Table S2). Changes in mitochondrial proteome were not influenced by a switch in muscle-fiber-type composition, since the “muscle fiber ratio”43 comparing fast- over slow-twitch fibers remained unaltered (Figure S6D).
To validate changes induced by UA on proteins related to mitophagy and mitochondrial function, we performed targeted western blot analysis on muscle-biopsy samples from the same study subjects. Targeted immunoblotting of UBE2N confirmed its increase with UA at 500 mg when comparing post- with pre-treatment (Figures S7A and S7B). At the same 500 mg dose, UA also increased levels of phospho-Parkin (Ser65), the fraction of active Parkin translocated on mitochondria and phosphorylated by PINK1 upon mitophagy activation (Figures 5D, 5E, and S7C). This supports the proteomics data indicating that UA activates PINK1/Parkin-mediated mitophagy in the human skeletal muscle.
Together with its benefit on mitochondrial health, UA also reduced plasma biomarkers of inflammation. The reduction of the CRP by UA is particularly relevant, as circulating CRP concentration is positively associated with an increased risk of age-related diseases and with poorer immune health.34 ,35 Of note, plasma CRP levels are also inversely correlated with muscle mitochondrial oxidative capacity.59
These biomarker data indicate how UA supplementation offers a potential dual benefit for muscle health, by improving mitochondrial function, while also acting to reduce age-related chronic inflammation, or inflamm-aging.60
UA induction of mitophagy could potentially mediate its anti-inflammatory effect, as removing dysfunctional mitochondria reduces the production of reactive oxygen species (ROS) and the release of mtDNA and cardiolipins, known triggers of inflammatory responses.50,61
Our data revealed UA to impact markers of Parkin-mediated mitophagy and to dose-dependently upregulate levels of mitochondrial TCA cycle and OXPHOS proteins.
In turn, UA-mediated reduction of inflammatory markers could contribute to blunting their negative regulation of mitochondrial biogenesis effectors, such as PGC1a and SIRT1, thereby allowing the generation of new mitochondria.61,62 How UA impacts both mitochondrial health and inflammation is an intriguing question that warrants in-depth mechanistic studies in more suited experimental models.
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