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Circulating Cell-Free Mitochondrial DNA: A Potential Blood-Based Biomarker for Sarcopenia in Patients Undergoing
Zhen Fan1, Yi Guo2, Xiao-Yi Zhong3
1Department of Geriatrics, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China (mainland).
Abstract:
BACKGROUND Mitochondrial impairment and exaggerated inflammation are hallmarks of sarcopenia. Recently, cell-free mitochondrial DNA (cf-mtDNA) has been in the spotlight as an endogenous danger molecule that can potentially elicit inflammation. Yet, its actual impact on sarcopenia, especially in patients with maintenance hemodialysis (MHD), is still at an early stage of investigation. MATERIAL AND METHODS A total of 105 MHD patients were enrolled in this study. The subjects were classified into sarcopenia group (SP) and non-sarcopenia group (NSP) according to the DXA scan and grip strength. Plasma and peripheral blood mononuclear cells (PBMCs) were separated from whole blood. Circulating cf-mtDNA (ccf-mtDNA) was detected using Taq Man RT-qPCR. Cytosolic mtDNA and inflammation- and mitophagy-related genes in PBMCs were quantitated using SYBR Green RT-qPCR. ΔΨm was analyzed using the fluorescent probe JC-1. RESULTS ccf-mtDNA content was significantly higher in SP group than in NSP group. Multivariate regression analysis showed a significant correlation of ccf-mtDNA with sarcopenia after adjusting for potential confounders. A similar trend of increased mtDNA was also observed in the mitochondria-free cytoplasm of PBMCs from SP patients, together with higher expression of TLR9 and IL-6 in this group. Next, using PBMCs as surrogates for mitochondria-rich cells, we found that ΔΨm was dramatically decreased in the SP group. In parallel, the mRNA levels of mitophagy-related genes Parkin and LAMP2 were increased in the SP group. CONCLUSIONS The results obtained demonstrated that ccf-mtDNA, as a potential driver of inflammatory component, may be involved in the pathogenesis of the MHD-related sarcopenia.
Insights
Cell-free mitochondrial DNA (cf-mtDNA) is elevated in hemodialysis patients with sarcopenia, suggesting it may drive inflammation and contribute to muscle loss in this population.
Area of Science:
- Mitochondrial Biology
- Immunology
- Geriatrics
Background:
- Sarcopenia, characterized by muscle loss, is linked to mitochondrial dysfunction and inflammation.
- Cell-free mitochondrial DNA (cf-mtDNA) is implicated as a pro-inflammatory molecule.
- The role of cf-mtDNA in sarcopenia, particularly in maintenance hemodialysis (MHD) patients, requires further investigation.
Purpose of the Study:
- To investigate the association between circulating cell-free mitochondrial DNA (ccf-mtDNA) and sarcopenia in MHD patients.
- To explore the relationship between cf-mtDNA, inflammation, and mitophagy in peripheral blood mononuclear cells (PBMCs) of MHD patients.
Main Methods:
- 105 MHD patients were categorized into sarcopenia (SP) and non-sarcopenia (NSP) groups.
- Quantified ccf-mtDNA using TaqMan RT-qPCR.
- Assessed cytosolic mtDNA, inflammation (TLR9, IL-6), and mitophagy (Parkin, LAMP2) gene expression in PBMCs via SYBR Green RT-qPCR.
- Measured mitochondrial membrane potential (ΔΨm) using JC-1.
Main Results:
- ccf-mtDNA levels were significantly higher in the SP group compared to the NSP group.
- Multivariate analysis confirmed a correlation between ccf-mtDNA and sarcopenia, independent of confounders.
- SP patients exhibited increased cytosolic mtDNA and elevated TLR9 and IL-6 expression in PBMCs.
- Reduced ΔΨm and increased mitophagy gene expression (Parkin, LAMP2) were observed in PBMCs from SP patients.
Conclusions:
- Elevated ccf-mtDNA is associated with sarcopenia in MHD patients.
- ccf-mtDNA may act as a pro-inflammatory factor contributing to the pathogenesis of sarcopenia in MHD.
- Mitochondrial dysfunction and altered mitophagy pathways are implicated in MHD-related sarcopenia.
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