TNF α Mediates the Interaction of Telomeres and Mitochondria Induced by Hyperglycemia: A Rural Community-Based Cross-Sectional Study

Abstract

This study is aimed at evaluating the relationship between leukocyte telomere length (LTL) and mitochondrial DNA copy number (mtDNAcn) in a noninterventional rural community of China with different glucose tolerance statuses. In addition, we investigate whether the indicators of oxidative stress and inflammation were involved and identify mediators among them. A total of 450 subjects in rural China were included and divided into two groups according to a 75 g oral glucose tolerance test (OGTT): the abnormal glucose metabolism (AGM, n=257, 57.1%) group and the normal glucose tolerance (NGT, n=193, 42.9%) group. Indicators of oxidative stress (superoxide dismutase (SOD) and glutathione reductase (GR)) and inflammatory indices (tumor necrosis factor α (TNFα) and interleukin-6 (IL-6)) were all determined by ELISA. LTL and mtDNAcn were measured using a real-time PCR assay. Linear regressions were used to adjust for covariates that might affect the relationship between LTL and mtDNAcn. Mediation analyses were utilized to evaluate the mediators. In the AGM, LTL was correlated with mtDNAcn (r=0.214, p=0.001), but no correlation was found in the NGT. The association between LTL and mtDNAcn was weakened after adjusting for inflammatory factors in the AGM (p=0.087). LTL and mtDNAcn were both inversely related to HbA1c, IL-6, TNFα, and SOD activity. Mediation analysis demonstrated that TNFα was a significant mediator in the telomere-mitochondrial interactome in the AGM. This result suggests that inflammation and oxidative stress may play a vital role in telomere shortening as well as mitochondrial dysfunction. In the subjects with hyperglycemia, a significant positive correlation is observed between LTL and mtDNAcn, which is probably mediated by TNFα. TNFα may be considered a potential therapeutic target against aging-related disease in hyperglycemia.