Mitochondrial impairment and repair in the pathogenesis of systemic lupus erythematosus

Abstract

Nucleic acid autoantibodies, increase type I interferon (IFN-α) levels, and immune cell hyperactivation are hallmarks of systemic lupus erythematosus (SLE). Notably, immune cell activation requires high level of cellular energy that is predominately generated by the mitochondria. Mitochondrial reactive oxygen species (mROS), the byproduct of mitochondrial energy generation, serves as an essential mediator to control the activation and differentiation of cells and regulate the antigenicity of oxidized nucleoids within the mitochondria. Recently, clinical trials on normalization of mitochondrial redox imbalance by mROS scavengers and those investigating the recovery of defective mitophagy have provided novel insights into SLE prophylaxis and therapy. However, the precise mechanism underlying the role of oxidative stress-related mitochondrial molecules in skewing the cell fate at the molecular level remains unclear. This review outlines distinctive mitochondrial functions and pathways that are involved in immune responses and systematically delineates how mitochondrial dysfunction contributes to SLE pathogenesis. In addition, we provide a comprehensive overview of damaged mitochondrial function and impaired metabolic pathways in adaptive and innate immune cells and lupus-induced organ tissues. Furthermore, we summarize the potential of current mitochondria-targeting drugs for SLE treatment. Developing novel therapeutic approaches to regulate mitochondrial oxidative stress is a promising endeavor in the search for effective treatments for systemic autoimmune diseases, particularly SLE.

Mitochondrial bioenergetic changes in systemic lupus erythematosus immune cell subsets: Contributions to pathogenesis and clinical applications

“… 25 , 26 While mtROS production is beneficial to many cellular processes, aberrantly increased production of mtROS during chronic inflammation can begin to affect the mitochondria itself. 27 For example, in inflammatory macrophages, excess mtROS are both produced by mitochondria, as well as target them. This causes mtDNA leakage which then functions in the capacity of a DAMP ( Figure 2 ).…”

Redefining Autoimmune Disorders’ Pathoetiology: Implications for Mood and Psychotic Disorders’ Association with Neurodegenerative and Classical Autoimmune Disorders

“…Raised cerebrospinal fluid and plasma indicants of autophagy and mitophagy, including PINK1 and parkin, are evident in the active phase of relapse remitting multiple sclerosis, with autophagy inhibition enhancing myelination, highlighting that the enhancement, as well as the suppression, of mitophagy are aspects of 'autoimmune' disorders [53]. Dysregulated mitophagy is evident in many classical 'autoimmune' disorders, including rheumatoid arthritis [54], SLE [55], T1DM [56], myasthenia gravis [57] and autoimmune hepatitis [58], as well as in suspected 'autoimmune' conditions, such as endometriosis [59], and neurodegenerative conditions [60]. Notably, alterations in mitochondrial function and mitophagy are not always evident in cells classically associated with these conditions, but in cells relevant to wider intercellular interactions, including immune cell mitochondria, as evident in Treg in myasthenia gravis [57].…”

Systemic Lupus Erythematosus Serum Stimulation of Human Intestinal Organoids Induces Changes in Goblet Cell Differentiation and Mitochondrial Fitness

“…We wanted to understand which other effects SLE serum would have on epithelial cells. Our focus was to investigate the influence of SLE stimulation on mitochondria, as these organelles are implicated in SLE pathogenesis 46,47 and serve as crucial regulators in maintaining intestinal homeostasis 48,49 . The term mitochondrion represented 10% of all DEGs (Fig.…”