Reduced mitochondrial-encoded NADH dehydrogenase 6 gene expression drives inflammatory CD4+T cells in patients with systemic lupus erythematosus

Abstract

Abnormal mitochondrial function has been implicated in the progression of systemic lupus erythematosus (SLE), the prototypical autoimmune disease, yet the underlying cause remains unclear. In this study, mitochondrial-encoded NADH dehydrogenase 6 gene (MT-ND6) was identified as having increased m⁶A methylation and decreased expression in peripheral blood mononuclear cells of SLE patients by MeRIP-seq analysis. MT-ND6 expression was negatively correlated with SLE disease activity index score and 24-h urine protein level, and lower in patients with positive anti-Sm or anti-dsDNA antibodies. With the reduction of MT-ND6 levels, CD4⁺ T cells in SLE patients exhibited mitochondrial dysfunction, as evidenced by increased levels of reactive oxygen species (ROS) and mitochondrial ROS and insufficient ATP production. Accordingly, in vitro MT-ND6 silencing induced abnormalities in the above mitochondrial indicators in CD4⁺ T cells, and promoted the development of both transcription and inflammatory factors in these cells. In contrast, treatment with targeted mitochondrial antioxidants largely counteracted the silencing effect of MT-MD6. Thus, reduced MT-ND6 in SLE patients may lead to mitochondrial dysfunction through ROS overproduction, thereby promoting inflammatory CD4⁺ T cells.