Mitochondrial DNA mutation m.3243A>G is associated with altered mitochondrial function in peripheral blood mononuclear cells, with heteroplasmy levels and with clinical phenotypes

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 HbA 1c , 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.

ATF5, a putative therapeutic target for the mitochondrial DNA 3243A > G mutation-related disease

“…Our results provided supports to the emerging role of m.3243A > G in bone mineralization deficiency. We and another group recently reported that m.3243A > G mutation was associated with loss of bone density in affected patients [11,12]. In the current study, we further confirmed this newly characterized pathological phenotype (Table 1), and started to unveil the underlying signaling pathways linking the m.3243A > G mutation to the loss of bone density.…”

“…Interestingly, a previous case-control study indicated that the m.3243A > G mutation is associated with premature bone aging, characterized by reduced bone mass, impaired structure and strength [11]. Our recent study further suggested that high levels of the m.3243A > G mutation in blood leukocytes were significantly associated with lower bone mineral density [12].…”

De Novo Mutation of m.3243A>G together with m.16093T>C Associated with Atypical Clinical Features in a Pedigree with MIDD Syndrome

“…Mitochondrial function evaluation was performed as previously described [19]. A total of 4 ml venous blood samples from each individual in F1957 were collected into vacuum tubes containing EDTA.…”

A point mutation of mitochondrial genes in diabetes and deafness with focal segmental glomerular sclerosis

“…The other manifestations of m.3243A>G in MIDD contained the following, namely central neurological and psychiatric features, ophthalmic disease, myopathy, cardiac disorders, renal disease. endocrine disease, gastrointestinal disease, and miscellaneous features [9].…”