Circulating Cell-Free Mitochondrial DNA: A Potential Blood-Based Biomarker for Sarcopenia in Patients Undergoing Maintenance Hemodialysis

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/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 into geriatric health: primary sarcopenia and innate immunity dynamics, examining SARC-F, serum TLR 4, TLR 9, and resolvin levels

“…Especially in chronic inflammatory conditions, mitochondrial DNA is released into plasma and serum as a result of cell stress and tissue damage and leads to activation of inflammation by using TLR 9 pathway with increasing serum levels [13]. In a study conducted by Zhen Fan et al in 2022, it was reported that serum cell free mitochondrial DNA level was significantly higher in the group with sarcopenia than in the group without sarcopenia in a population of 105 patients undergoing haemodialysis as renal replacement therapy due to chronic renal failure [14]. Sarcopenia is an age-related syndrome marked by the loss of muscle mass and function, with unclear mechanisms.…”

The Diagnostic, Prognostic, and Therapeutic Potential of Cell-Free DNA with a Special Focus on COVID-19 and Other Viral Infections

“…cf-mtDNA exists in different biofluids, such as urine [ 83 ], blood [ 84 ], saliva [ 81 ], cerebrospinal [ 85 ], and follicular fluid [ 86 ]. MtDNA is supposed to be more prone to damage than nuclear DNA.…”

Roles of Mitochondrial DNA Damage in Kidney Diseases: A New Biomarker

“…Plasma mtDNA is a strong predictor of cardiovascular events as well as the need for hospitalization in patients with peritoneal dialysis [ 64 ]. In patients undergoing maintenance hemodialysis (MHD), circulating mtDNA contents were significantly higher in sarcopenia patients, together with higher TLR9 and IL-6 expression, which demonstrated that mtDNA could be involved in the pathogenesis of MHD-related sarcopenia [ 65 ]. As one of the indispensable proteins encoded by mtDNA, serum ND6 was increased in active antineutrophil cytoplasmic antibody-associated vasculitis, and ND6 concentration was negatively correlated with the percentage of normal glomeruli in kidney biopsies [ 66 ].…”