Search

Abstract Mitochondrial DNA copy number (mtDNA-CN) is a biomarker for mitochondrial dysfunction associated with several diseases. Previous genome-wide association studies (GWAS) have been performed to unravel underlying mechanisms of mtDNA-CN regulation. However, the identified gene regions explain only a small fraction of mtDNA-CN variability. Most of this data has been estimated from microarrays based on various pipelines. In the present study we aimed to (1) identify genetic loci for qPCR-measured mtDNA-CN from three studies (16,130 participants) using GWAS, (2) identify potential systematic differences between our qPCR derived mtDNA-CN measurements compared to the published microarray intensity-based estimates, and (3) disentangle the nuclear from mitochondrial regulation of the mtDNA-CN phenotype. We identified two genome-wide significant autosomal loci associated with qPCR-measured mtDNA-CN: at HBS1L (rs4895440, p = 3.39 × 10–13) and GSDMA (rs56030650, p = 4.85 × 10–08) genes. Moreover, 113/115 of the previously published SNPs identified by microarray-based analyses were significantly equivalent with our findings. In our study, the mitochondrial genome itself contributed only marginally to mtDNA-CN regulation as we only detected a single rare mitochondrial variant associated with mtDNA-CN. Furthermore, we incorporated mitochondrial haplogroups into our analyses to explore their potential impact on mtDNA-CN. However, our findings indicate that they do not exert any significant influence on our results.

Mitochondrial dysfunction is a common occurrence in the aging process and is observed in diseases such as age-related macular degeneration (AMD). Increased levels of reactive oxygen species lead to damaged mitochondrial DNA (mtDNA), resulting in dysfunctional mitochondria, and, consequently, mtDNA causes further harm in the retinal tissue. However, it is unclear whether the effects are locally restricted to the high-energy-demanding retinal pigment epithelium or are also systematically present. Therefore, we measured mtDNA copy number (mtDNA-CN) in peripheral blood using a qPCR approach with plasmid normalization in elderly participants with and without AMD from the AugUR study (n = 2262). We found significantly lower mtDNA-CN in the blood of participants with early (n = 453) and late (n = 170) AMD compared to AMD-free participants (n = 1630). In regression analyses, we found lower mtDNA-CN to be associated with late AMD when compared with AMD-free participants. Each reduction of mtDNA-CN by one standard deviation increased the risk for late AMD by 24%. This association was most pronounced in geographic atrophy (OR = 1.76, 95% CI 1.19–2.60, p = 0.004), which has limited treatment options. These findings provide new insights into the relationship between mtDNA-CN in blood and AMD, suggesting that it may serve as a more accessible biomarker than mtDNA-CN in the retina.

Oxidative stress (OS) and inflammation are features of metabolic syndrome (MetS) that can contribute to the shortening of telomere length (TL), a marker of cellular ageing. Research indicates that exercise can positively influence MetS-associated conditions and TL. However, the effects of low-volume exercise types on TL are still unknown. We investigated the impact of very-low-volume high-intensity interval training (LV-HIIT), one-set resistance training (1-RT), and whole-body electromyostimulation (WB-EMS) on TL, inflammation, and cardiometabolic indices in 167 MetS patients. Data were derived from two randomized controlled trials where patients were allocated to an exercise group (2 sessions/week, for 12 weeks) or a control group. All groups received standard-care nutritional weight loss counselling. TL was determined as the T/S ratio (telomere to single-copy gene amount). All groups significantly reduced body weight (p < 0.05), but the T/S-ratio (p < 0.001) only increased with LV-HIIT. OS-related inflammatory markers (C-reactive protein, interleukin-6, and lipopolysaccharide-binding protein) only decreased (p < 0.05) following LV-HIIT. The MetS severity z-score improved with LV-HIIT (p < 0.001) and 1-RT (p = 0.014) but not with WB-EMS. In conclusion, very-low-volume exercise modalities have differential effects on telomeres, inflammation, and cardiometabolic health. Only LV-HIIT but not strength-based low-volume exercise increased TL in MetS patients, presumably due to superior effects on OS-related inflammatory markers.