Mitochondria as a key player in systemic lupus erythematosus.

Abstract

Systemic lupus erythematosus (SLE) is a heterogeneous, multisystemic autoimmune disease with a broad clinical spectrum. Loss of self-tolerance and chronic inflammation are critical markers of SLE pathogenesis. Although alterations in adaptive immunity are widely recognized, increasing reports indicate the role of mitochondrial dysfunction in activating pathogenic pathways involving the innate immune system. Among these, disarrangements in mitochondrial DNA copy number and heteroplasmy percentage are related to SLE activity. Furthermore, increased oxidative stress contributes to post-translational changes in different molecules (proteins, nucleic acids, and lipids), release of oxidized mitochondrial DNA through a pore of voltage-dependent anion channel oligomers, and spontaneous mitochondrial antiviral signaling protein oligomerization. Finally, a reduction in mitophagy, apoptosis induction, and NETosis has been reported in SLE. Most of these pathways lead to persistent and inappropriate exposure to oxidized mitochondrial DNA, which can stimulate plasmacytoid dendritic cells, enhance autoreactive lymphocyte activation, and release increased amounts of interferons through stimulation of toll-like receptors and cytosolic DNA sensors. Likewise, abnormal T-cell receptor activation, decreased regulatory T cells, enhanced Th17 phenotypes, and increased monocyte maturation to dendritic cells have also been observed in SLE. Targeting the players involved in mitochondrial damage can ultimately help.