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- Title
Mitochondrial DNA mutation m.3243A>G is associated with altered mitochondrial function in peripheral blood mononuclear cells, with heteroplasmy levels and with clinical phenotypes.
- Authors
Geng, X.; Zhang, Y.; Yan, J.; Chu, C.; Gao, F.; Jiang, Z.; Zhang, X.; Chen, Y.; Wei, X.; Feng, Y.; Lu, H.; Wang, C.; Zeng, F.; Jia, W.
- Abstract
Aims: To investigate the associations among heteroplasmy levels (i.e. the proportions of mutant and wild‐type mitochondrial DNA in the same cell), mitochondrial function and clinical severity of the m.3243A>G mutation. Methods: A total of 17 participants carrying the m.3243A>G mutation and 17 sex‐ and age‐matched healthy controls were included in this study. Heteroplasmy levels of the m.3243A>G mutation in leukocytes, saliva and urine sediment were determined by pyrosequencing. The clinical evaluation included endocrinological, audiological and ophthalmological examinations. Mitochondrial function was determined in peripheral blood mononuclear cells isolated from participants. Results: Heteroplasmy levels in urine sediment were higher than those in leukocytes and saliva. Reduced levels of adenosine triphosphate and mitochondrial membrane potential, and increased reactive oxygen species production were observed in mutant peripheral blood mononuclear cells (all P < 0.05). Linear regression analysis indicated that higher heteroplasmy levels in peripheral blood leukocytes were associated with increased levels of glycated albumin and HbA1c, and decreased total hip bone mineral density T‐score after adjustment for age and sex (all P < 0.05). Furthermore, mitochondrial membrane potential was independently associated with bone mineral density T‐score at the femoral neck (P < 0.05). Conclusions: Heteroplasmy levels in peripheral blood leukocytes and mitochondrial membrane potential in peripheral blood mononuclear cells were closely associated with clinical manifestations and were valuable for evaluation of the clinical severity of the m.3243A>G mutation. What's new?: The m.3243A>G mutation in the tRNALeu (UUR) gene is one of the most common human pathogenic mitochondrial DNA point mutations; however, the associations among mitochondrial function, clinical phenotypes and heteroplasmy levels of the m.3243A>G mutation remain unclear.We first reported significant mitochondrial dysfunction in peripheral blood mononuclear cells (PBMCs) isolated from m.3243A>G mutation carriers.Linear regression analysis then showed that heteroplasmy levels in peripheral blood leukocytes and mitochondrial membrane potential in PBMCs were helpful for predicting severity of the disease.
- Subjects
REACTIVE oxygen species; ADENOSINE triphosphate; BIOLOGICAL transport; DNA; GLYCOSYLATED hemoglobin; MITOCHONDRIA; GENETIC mutation; REGRESSION analysis; SERUM albumin; PHENOTYPES; BONE density; MONONUCLEAR leukocytes; SEQUENCE analysis
- Publication
Diabetic Medicine, 2019, Vol 36, Issue 6, p776
- ISSN
0742-3071
- Publication type
Article
- DOI
10.1111/dme.13874