Abstract
The role of mitochondrial DNA (mtDNA) alterations in the pathophysiology of systemic lupus erythematosus (SLE) remains unclear. We investigated sequence variations in the D310 region and copy number change of mtDNA in 85 SLE patients and 45 normal subjects. Leukocyte DNA and RNA were extracted from leukocytes of the peripheral venous blood. The D310 sequence variations and copy number of mtDNA, and mRNA expression levels of mtDNA-encoded genes in leukocytes were determined by quantitative real-time polymerase chain reaction (Q-PCR) and PCR-based direct sequencing, respectively. We found that leukocyte mtDNA in SLE patients exhibited higher frequency of D310 heteroplasmy (69.4% vs. 48.9%, p = 0.022) and more D310 variants (2.2 vs. 1.7, p = 0.014) than those found in controls. Among normal controls and patients with low, medium or high SLE disease activity index (SLEDAI), an ever-increasing frequency of D310 heteroplasmy was observed (p = 0.021). Leukocyte mtDNA copy number tended to be low in patients of high SLEDAI group (p = 0.068), especially in those harboring mtDNA with D310 heteroplasmy (p = 0.020). Moreover, the mtDNA copy number was positively correlated with the mRNA level of mtDNA-encoded ND1 (NADH dehydrogenase subunit 1) (p = 0.041) and ATPase 6 (ATP synthase subunit 6) (p = 0.030) genes. Patients with more D310 variants were more susceptible to lupus nephritis (p = 0.035). Taken together, our findings suggest that decrease in the mtDNA copy number and increase in D310 heteroplasmy of mtDNA are related to the development and progression of SLE, and that the patients harboring more D310 variants of mtDNA are more susceptible to lupus nephritis.
Highlights
Systemic lupus erythematosus (SLE) is a prototype of autoimmune disease characterized by the dysfunction of immunocompetent cells with the production of protean pathogenic auto-antibodies that lead to multiple arrays of major organ injuries [1]
With D310 heteroplasmy in mitochondrial DNA (mtDNA) of the leukocytes, we found a negative correlation between the mtDNA copy number and SLE Disease Activity Index (SLEDAI) score (p = 0.020, Pearson’s correlation coefficient γpcc = −0.268); (C) Among the 44 analyzed SLE patients, a positive correlation was found between mtDNA copy numbers and the mRNA expression levels of mtDNA-encoded ND1 gene; (D) Among the 44 analyzed SLE patients, a positive correlation was found between mtDNA copy numbers and the mRNA expression levels of mtDNA-encoded ATPase 6 gene
We demonstrated that the frequency of leukocyte D310 heteroplasmy was increased and the copy number of leukocyte mtDNA was decreased in SLE patients as their disease worsened (Table 2, Figure 2A)
Summary
Systemic lupus erythematosus (SLE) is a prototype of autoimmune disease characterized by the dysfunction of immunocompetent cells with the production of protean pathogenic auto-antibodies that lead to multiple arrays of major organ injuries [1]. The mtDNA copy number in a human tissue is dynamic and may vary widely with cell type and the physiological condition [13]. The number of C before T is highly variable with a range from 6 to 12 (C6, C7, C8, C9, C10, C11, C12), and 7 or 8 (C7 or C8, wild-type) being the most common ones [10] These variations with a T shifting over np 310 (originated from a deletion or insertion) in mtDNA are referred to as D310 polymorphism or D310 sequence variations. We examined the differences in the copy number and D310 sequence variations of mtDNA in leukocytes of SLE patients and normal subjects. We investigated whether these differences are associated with clinical manifestations of SLE
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