One more datapoint in favor of our future Nobel prize @John_Hemming: Mitochondrial dysfunction-mediated metabolic remodeling of TCA cycle promotes Parkinson’s disease through inhibition of H3K4me3 demethylation 2025
(that being said, unfortunately it’s a group of weak Chinese universities + one Italian researcher)
Parkinson’s disease (PD), a neurodegenerative disorder caused by complex factors, is usually associated to mitochondrial dysfunctions but the links between such disorder and PD remain object of research. Here, we report that impaired mitochondrial quality control (MQC) system is a molecular basis of the mitochondrial dysfunction in PD and that tricarboxylic acid cycle (TCA cycle) disorder is the main feature of such mitochondrial dysfunction. Multi-omics analysis revealed that MDH2, OGDHL and IDH3G enzymes are bottlenecks in the enzymatic reactions of the TCA cycle in PD. Mechanistically, the abnormal α-KG/fumarate ratio caused by the TCA cycle bottleneck inhibits histone H3K4me3 demethylation and further enhances the expression of alpha-synuclein (SNCA), which may promote PD at an early stage. On these bases, we proposed a number of PD therapeutic strategies targeting mitochondria and histone methylation modifications, which proved to be effective in in vitro or in vivo models, especially citrate supplementation, in restoring normal TCA cycle enzymatic reactions. Taken together, our work highlights the non-negligible regulatory role of “mitochondrial-nuclear” communication in PD and provides important insights for the development of PD therapeutic strategies.
Citrate exhibits neuroprotective effects by correcting the abnormal α-KG/Fumarate ratio in PD
Based on the above results, we sought to find a natural supplement to correct the abnormal TCA cycle in PD. Given the extraordinary potential of citrate supplementation in improving cognitive ability, we constructed a subacute PD mouse model using MPTP and supplemented citrate through drinking water (Fig. 6A), which maximally simulated the dietary intake of natural supplements under physiological conditions [21]. Although continuous intraperitoneal injection of MPTP during model construction affected the food intake of mice, and this effect was reflected in changes in mouse body weight, the weight difference became no longer significant in the later stages of the model construction (Fig. 6B, C). During the establishment of the model, the water intake of mice was not affected, which ensured the stability of citrate supplementation (Fig. 6D). As expected, dietary citrate supplementation did not show systemic toxicity, while significantly increasing serum and midbrain citrate levels, confirming the safety and effectiveness of the citrate supplementation model, especially that citrate can cross the blood-brain barrier (BBB) and enter the midbrain (Fig. 6E, F). To evaluate the effect of citrate on motor dysfunction in the subacute PD model, we tested the motor ability and coordination ability of the model mice by behavioral tests. Compared with MPTP-treated mice, citrate supplementation reduced the time mice spent on the pole and increased the grasping time of mice on the inverted grid (Fig. 6G, H), indicating that citrate supplementation alleviated motor impairment in PD mice. Importantly, citrate supplementation restored the impaired tyrosine hydroxylase (TH; DaN marker) protein expression in the SN of PD mice and reduced MPTP-induced SNCA accumulation in the midbrain (Fig. 6I–K).
Currently, about the TCA cycle, supplementation of multiple metabolites including isocitrate [36] and α-KG [37] has been reported to show neuroprotective effects in PD. Based on the metabolic bottleneck of the TCA cycle reported here, we propose citrate as a potential metabolite for the treatment of PD. Actually, citrate can cross the BBB and shows good prospects in improving memory and treating Alzheimer’s disease [38,39,40]. At the same time, citrate, as α-KG precursor, acts as a metabolic supplement to help increase α-KG levels. More importantly, citrate can also act as a metabolic activator to enhance the activity of MDH2 in a high malate environment, promoting the conversion of fumarate metabolite malate to oxaloacetate [41], which reduces the accumulation of its substrate fumarate. Taken together, the multiple effects of citrate help reduce the α-KG/Fumarate ratio and correct abnormal TCA cycle flux, making it a very promising natural candidate for the treatment of PD. Previous reports have highlighted SNCA accumulation as an upstream event that triggers mitochondrial damage [42]. Here, our work emphasizes mitochondrial damage as an early factor in the pathogenesis of PD, and SNCA accumulation as a downstream molecular event that is finely regulated by α-KG/Fumarate ratio and H3K4me3 levels. These works reflect the complex crosstalk in the pathogenesis of PD and provide a more comprehensive perspective for the development of therapeutic strategies.
Briefly, mice (8 weeks old) received 12 days of daily drinking water containing citrate (Sigma; 1% w/v) and intraperitoneal injection (i. p.) of MPTP (MedChemExpress, HY-15608; 30 mg/kg body weight) or vehicle treatment for 8th to 12th days; the behavioral teste and sampling were performed three days after the last injection. Citrate was dissolved in drinking water, with pH adjusted to 7.3–7.4 by addition of sodium hydroxide.
They used the same dose as the paper Dietary citrate supplementation enhances longevity, metabolic health, and memory performance through promoting ketogenesis, which, according to ChatGPT, is equivalent to 8–10 g/day for a 70-kg human.
