Pathological mechanisms of abnormal iron metabolism and mitochondrial dysfunction in systemic lupus erythematosus

Abstract

Introduction: Systemic lupus erythematosus [SLE] is a chronic, autoimmune condition characterized by the formation of autoantibodies directed against nuclear components and by oxidative stress. Recently, a number of studies have demonstrated the essential role of iron in the immune response and there is growing evidence that abnormal iron homeostasis can occur in the chronic inflammatory state seen in SLE. Not only is iron vital for hematopoiesis, it is also important for a number of other key physiological processes, in particular in maintaining healthy mitochondrial function.Areas covered: In this review, we highlight the latest understanding with regards to how patients with SLE may be at risk of cellular iron depletion as a result of both absolute and functional iron deficiency. Furthermore, we aim to explain the latest evidence of mitochondrial dysfunction in the pathogenesis of the disease.Expert opinion: Growing evidence suggests that both abnormal iron homeostasis and subsequent mitochondrial dysfunction can impair effector immune cell function. Through a greater understanding of these abnormalities, therapeutic options that directly target iron and mitochondria may ultimately represent novel treatment targets that may translate into clinical care of patients with SLE in the near future.

Keywords: Ferroptosis; Iron; functional iron deficiency; immunometabolism; mitochondria; systemic lupus erythematosus.

Figure 1.

Free ferric (Fe3+) iron is bound to the transporter protein, transferrin, in the circulation. Transferrin bound iron can then enter the cell through the membrane transferrin receptor (TfR). Iron is exported from the cell by Ferroportin (FPN). Excessive free iron may be sequestered by lipocalin, which is released on innate immune system activation. Iron may also be bound to soluble transferrin receptors (sTfR) in the circulation. Fe, Free Ferric (Fe3+) iron; FPN, Ferroportin; Tf, Transferrin; TfR, Transferrin receptor; sTfR, soluble transferrin receptor; LCN-2, Lipocalin-2

Figure 2.

The electron transport chain on the inner mitochondrial membrane is the primary site of ATP production as a result of oxidative phosphorylation. The chain is comprised of five separate complexes that conduct a number of processes that generates an electrochemical proton gradient across the membrane, which in turn catalyses the generation of ATP from ADP. Complex I, II and III contain iron molecules in the form of iron sulfur cluster. FMN, Flavin mononucleotide; NAD+, Nicotinamide adenine dinucleotide; NADH, Nicotinamide adenine dinucleotide hydrogen; H+, Hydrogen; Fe-S, Iron-sulfide cluster; Cyt, Cytochrome; UQ, Ubiquinone; FAD, Flavin adenine dinucleotide; Cu, copper; ATP, adenosine triphosphate; ADP, adenosine diphosphate

Figure 3.

Abnormalities of iron metabolism in SLE