RE: Mitochondrien - 17

Associations between Circulating Biomarkers of One-Carbon Metabolism and Mitochondrial D-Loop Region Methylation Levels

Zitat

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Background/Objectives: One-carbon metabolism is a critical pathway for epigenetic mechanisms. Circulating biomarkers of one-carbon metabolism have been associated with changes in nuclear DNA methylation levels in individuals affected by age-related diseases. More and more studies are showing that even mitochondrial DNA (mtDNA) could be methylated. In particular, methylation of the mitochondrial displacement (D-loop) region modulates the gene expression and replication of mtDNA and, when altered, can contribute to the development of human illnesses. However, no study until now has demonstrated an association between circulating biomarkers of one-carbon metabolism and D-loop methylation levels. Methods: In the study presented herein, we searched for associations between circulating one-carbon metabolism biomarkers, including folate, homocysteine, and vitamin B12, and the methylation levels of the D-loop region in DNA obtained from the peripheral blood of 94 elderly voluntary subjects. Results: We observed a positive correlation between D-loop methylation and vitamin B12 (r = 0.21; p = 0.03), while no significant correlation was observed with folate (r = 0.02; p = 0.80) or homocysteine levels (r = 0.02; p = 0.82). Moreover, D-loop methylation was increased in individuals with high vitamin B12 levels compared to those with normal vitamin B12 levels (p = 0.04). Conclusions: This is the first study suggesting an association between vitamin B12 circulating levels and mtDNA methylation in human subjects. Given the potential implications of altered one-carbon metabolism and mitochondrial epigenetics in human diseases, a deeper understanding of their interaction could inspire novel interventions with beneficial effects for human health.

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https://www.mdpi.com/2075-4655/8/4/38

Mitochondria break free: Mitochondria-derived vesicles in aging and associated conditions
https://www.sciencedirect.com/science/ar...568163724003672

Human iPSCs from Aged Donors Retain Their Mitochondrial Aging Signature
https://www.mdpi.com/1422-0067/25/20/11199

Mitochondrial fatty acid oxidation drives senescence
https://pubmed.ncbi.nlm.nih.gov/39454000/

Transfer of mitochondrial DNA into the nuclear genome during induced DNA breaks
https://www.nature.com/articles/s41467-024-53806-0

A nucleic acid prodrug activates mitochondrial respiration and extends lifespan
https://www.biorxiv.org/content/10.1101/...dV67CPVe_LbocyQ

Hallo Prometheus,

die bei der Studie verwendeten Substanzen können evtl. schwere Nebenwirkungen verursachen(?): https://www.biorxiv.org/content/10.1101/...3599v1.full.pdf .

Viele Grüße und einen schönen Tag

Roger

Zitat von Prometheus im Beitrag #409

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@Roger
Schon möglich, aber zumindest im Zytotoxizitäts-Assay haben die Substanzen sehr gut abgeschnitten.... Welche konkreten Nebenwirkungen erwartest du?

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Zitat

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Despite the evidence of the therapeutic effects of ATP derivatives, their efficacy remains controversial. Some reports suggest that ATP administration is ineffective as a pharmaceutical agent because of the limited blood stability of adenosine derivatives and the lack of cell membrane permeability of the negatively charged phosphate groups, hindering entry into cells. Furthermore, cells recognize extracellular ATP as an inflammatory signal. To minimize side effects, ATP administration techniques include drug delivery methods that encapsulate ATP in microparticles such as liposomes, micelles, and nanospheres21. Nevertheless, these approaches have limited utilization and applicability in the treatment of age-related diseases. Owing to the difficulty of increasing intracellular ATP concentrations, the long-term effects of ATP administration as a drug remain unclear.
Therefore, the present study was designed to develop the world’s first prodrug with enhanced biological stability and cellular permeability of adenosine phosphate, capable of stimulating AXP (adenosine monophosphate (AMP), adenosine diphosphate (ADP), and ATP)-associated metabolic pathways, boosting mitochondrial respiration, ATP production, and reducing aging

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https://www.biorxiv.org/content/10.1101/...3599v1.full.pdf

Dabei ist ja erklärt, dass der in der Studie genutzte Stoff gerade in Hinblick auf diese möglichen Probleme entwickelt wurde.

Hallo Prometheus,

es geht konkret um diese Substanzen und ich sehe das kritisch: mononucleoside analogs as a class of nucleoside-based antivirals, such as Sofosbuvir and Remdesivir,
targeting hepatitis C virus23, and COVID-1924.

Viele Grüße

Roger

Neuroinflammation in Age-Related Neurodegenerative Diseases: Role of Mitochondrial Oxidative Stress
https://www.mdpi.com/2076-3921/13/12/1440

Mitochondrial Dysfunction in Cardiac Disease: The Fort Fell
https://www.mdpi.com/2218-273X/14/12/1534

Fragmented Mitochondria Linked to Muscle Weakness
https://www.lifespan.io/news/fragmented-...uscle-weakness/

Fission: Mitochondrien teilen sich, die resultierenden neuen Mitochondrien sind oft kleiner und ggf. fragmentierter

Fusion: Wie der Name schon vermuten lässt, fusionieren hier zwei Mitochondrien und können ihr genetisches Material austauschen.

Mit zunehmendem Alter gibt es mehr Fission und weniger Fusion:

Aging shifts mitochondrial dynamics toward fission to promote germline stem cell loss

Zitat

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Changes in mitochondrial dynamics (fusion and fission) are known to occur during stem cell differentiation; however, the role of this phenomenon in tissue aging remains unclear. Here, we report that mitochondrial dynamics are shifted toward fission during aging of Drosophila ovarian germline stem cells (GSCs), and this shift contributes to aging-related GSC loss. We found that as GSCs age, mitochondrial fragmentation and expression of the mitochondrial fission regulator, Dynamin-related protein (Drp1), are both increased, while mitochondrial membrane potential is reduced. Moreover, preventing mitochondrial fusion in GSCs results in highly fragmented depolarized mitochondria, decreased BMP stemness signaling, impaired fatty acid metabolism, and GSC loss. Conversely, forcing mitochondrial elongation promotes GSC attachment to the niche. Importantly, maintenance of aging GSCs can be enhanced by suppressing Drp1 expression to prevent mitochondrial fission or treating with rapamycin, which is known to promote autophagy via TOR inhibition. Overall, our results show that mitochondrial dynamics are altered during physiological aging, affecting stem cell homeostasis via coordinated changes in stemness signaling, niche contact, and cellular metabolism. Such effects may also be highly relevant to other stem cell types and aging-induced tissue degeneration.

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https://onlinelibrary.wiley.com/doi/10.1111/acel.13191

Ein paar Ideen, die Fusion zu stärken (danke AI):

Betain: https://pmc.ncbi.nlm.nih.gov/articles/PMC7376439/

Xanthohumol (aus Hopfen) oder Liquiritigenin (aus Chinesischem Lakritz): https://pmc.ncbi.nlm.nih.gov/articles/PMC9968749/

#414
Fusion zu pushen um die Fragmentierung der Mitochondien zu begrenzen ist ja auch ein wichtiger Ansatz bei ME/CFS.


@version2
Bzgl. Fission und Fusion gab es damals einen langen Thread zu bei Longecity der aber schon lange nicht mehr upgedated wird. Bei Linkedin updated er das aber noch weiterhin ab und zu.
https://www.longecity.org/forum/topic/94...drial-dynamics/

Boosting neuronal activity-driven mitochondrial DNA transcription improves cognition in aged mice
https://www.science.org/doi/10.1126/scie...PLNhM9CcAya3gCw

Interessant der Effekt von Vitamin C hier.

Succinate Regulates Endothelial Mitochondrial Function and Barrier Integrity
https://www.mdpi.com/2076-3921/13/12/1579

Mitochondrial Dynamics in Brain Cells During Normal and Pathological Aging
https://www.mdpi.com/1422-0067/25/23/12855

Nuclear respiratory factor-1 (NRF1) induction as a powerful strategy to deter mitochondrial dysfunction and senescence in mesenchymal stem cells
https://onlinelibrary.wiley.com/doi/full...2J3UoKc_h3pPGlg

Quercetin preserves mitochondria-endoplasmic reticulum contact sites improving mitochondrial dynamics in aged myocardial cells
https://link.springer.com/article/10.1007/s10522-024-10174-y

Cellular Respiration: Mapping mitochondrial aging
https://elifesciences.org/articles/105191

Mitochondrial Flux, Biogenesis & Autophagy in the Pathophysiologie of Innate Immune System Dysfunction
https://www.preprints.org/manuscript/202412.2275/v1

Time-of-day control of mitochondria regulates NLRP3 inflammasome activation in macrophages
https://faseb.onlinelibrary.wiley.com/do.../fj.202400508RR

Higher skeletal muscle mitochondrial oxidative capacity is associated with preserved brain structure up to over a decade
https://www.nature.com/articles/s41467-024-55009-z

Inter- and intracellular mitochondrial communication: signaling hubs in aging and age-related diseases
https://cmbl.biomedcentral.com/articles/...ZEXXFkcPjfC9_-Q

Targeting Mitochondrial Dysfunction in Cerebral Ischemia: Advances in Pharmacological Interventions
https://www.mdpi.com/2076-3921/14/1/108

Hallo Prometheus,

der Wirkstoff Tetrazepam (Benzos) und NAC wären evtl. sehr gut geeignet. Tetrazepam (Tetrazepam haltige Medikamente sind in der EU seit dem 1.8.2013 außer Handel) verbessert die Schlafqualität erheblich, so dass die Schäden in der Nacht repariert werden können und NAC fördert u.a. die Bildung von Glutathion (höhere antioxidative Kapazität).

VG

Roger

Zitat von Roger im Beitrag #424

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Hallo Prometheus,

der Wirkstoff Tetrazepam (Benzos) und NAC wären evtl. sehr gut geeignet. Tetrazepam (Tetrazepam haltige Medikamente sind in der EU seit dem 1.8.2013 außer Handel) verbessert die Schlafqualität erheblich, so dass die Schäden in der Nacht repariert werden können und NAC fördert u.a. die Bildung von Glutathion (höhere antioxidative Kapazität).

VG

Roger

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