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Review
. 2022 Mar;36(7-9):462-479.
doi: 10.1089/ars.2021.0070. Epub 2022 Jan 4.

Redox Homeostasis Involvement in the Pharmacological Effects of Metformin in Systemic Lupus Erythematosus

Xiangyu Teng  1 , Josephine Brown  1 , Laurence Morel  1
Affiliations
Review

Redox Homeostasis Involvement in the Pharmacological Effects of Metformin in Systemic Lupus Erythematosus

Xiangyu Teng et al. Antioxid Redox Signal. 2022 Mar.

Abstract

Significance: Metformin has been proposed as a treatment for systemic lupus erythematosus (SLE). The primary target of metformin, the electron transport chain complex I in the mitochondria, is associated with redox homeostasis in immune cells, which plays a critical role in the pathogenesis of autoimmune diseases. This review addresses the evidence and knowledge gaps on whether a beneficial effect of metformin in lupus may be due to a restoration of a balanced redox state. Recent Advances: Clinical trials in SLE patients with mild-to-moderate disease activity and preclinical studies in mice have provided encouraging results for metformin. The mechanism by which this therapeutic effect was achieved is largely unknown. Metformin regulates redox homeostasis in a context-specific manner. Multiple cell types contribute to SLE, with evidence of increased mitochondrial oxidative stress in T cells and neutrophils. Critical Issues: The major knowledge gaps are whether the efficacy of metformin is linked to a restored redox homeostasis in the immune system, and if it does, in which cell types it occurs? We also need to know which patients may have a better response to metformin, and whether it corresponds to a specific mechanism? Finally, the identification of biomarkers to predict treatment outcomes would be of great value. Future Directions: Mechanistic studies must address the context-dependent pharmacological effects of metformin. Multiple cell types as well as a complex disease etiology should be considered. These studies must integrate the rapid advances made in understanding how metabolic programs direct the effector functions of immune cells. Antioxid. Redox Signal. 36, 462-479.

Keywords: ROS; lupus; metformin; mitochondria.

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Conflict of interest statement

No competing financial interests exist.

Figures

FIG. 1.
FIG. 1.
Pathogenesis of SLE. Autoreactive B cells with the help of autoreactive CD4+ T cells lead to the production of autoantibodies, which form IC with autoantigens formed by nucleic acid–protein complexes. Increased autoantigen production from apoptotic cells and neutrophil extracellular traps as well as deregulated clearance amplify the pathogenic cascade. pDCs secrete type I IFN in response to IC stimulation. Type I IFN activate immune cells. Autoreactive CD4+ T cells also contribute to inflammation by producing inflammatory cytokines. ICs deposit in tissues and along with inflammatory cytokines, cause damage and further autoantigen release. IC, immune complexes; IFN, interferon; pDCs, plasmacytoid dendritic cells; SLE, systemic lupus erythematosus. Color images are available online.
FIG. 2.
FIG. 2.
Mitochondrial mechanisms of action of metformin. Metformin is up taken into the cells mainly through the OCT1. Metformin inhibits the ETC complex I (NADH dehydrogenase) and mGPDH. By inhibiting ETC complex I, metformin suppresses oxidative phosphorylation and ATP production, which then activates AMPK and inhibits mTOR. The inhibition of mGPDH in the glycerol phosphate shuttle reduces the import of cytosolic NAD. AMPK, AMP-activated protein kinase; ATP, adenosine triphosphate; ETC, electron transport chain; mGPDH, mitochondrial glycerophosphate dehydrogenase; NAD, nicotinamide adenine dinucleotide; NADH, nicotinamide adenine dinucleotide + hydrogen; OCT1, organic cation transporter 1; mTOR, mammalian target of rapamycin. Color images are available online.
FIG. 3.
FIG. 3.
Metformin inhibits the transcription of ISGs in IFN-α–stimulated human CD4+ T cells. STAT1 phosphorylation and function downstream on the type I IFN receptor were reduced by metformin. The inhibition of the ISG response was achieved with other ETC inhibitors, indicating that the effect of metformin is not unique, and that mitochondrial respiration plays a crucial role in this process. The inhibition of ISG expression was independent of the AMPK/mTOR pathway. Therefore, the molecular link between decreased ETC activity and STAT1 activation is unknown. It is possible that the same mechanism that is responsible for inhibiting STAT3 is also responsible for inhibiting STAT1 activation in IFN-stimulated T cells. This could involve noncanonical functions of STAT3, which in turn regulate mitochondrial metabolism. Noncanonical functions of STAT1 have also been linked to mitochondrial oxidative stress. ISG, interferon-stimulated gene. Color images are available online.
FIG. 4.
FIG. 4.
Proposed modes of action of metformin on the main sources of ROS production. (A) Metformin reduces mROS generated by electrons leaked from the ETC during reverse electron transfer by inhibiting the ETC complex I and mGPDH. (B) Mitochondrial permeability transition pore formation is triggered in part by mROS, which generates a second wave of mROS through ROS-induced ROS release. Whether metformin has any effect on this process is unknown. (C) NOX in the plasma membrane generates cytoplasmic ROS. Metformin has not been reported to interfere with this process. NOX, NADPH-oxidase; ROS, reactive oxygen species; mROS, mitochondrial ROS. Color images are available online.
FIG. 5.
FIG. 5.
Proposed mechanism of metformin import into mitochondria. The transporter by which metformin accumulates in mitochondria has not been identified. It has been proposed that negatively charged MMP drives positively charged metformin into the mitochondria. The two methyl groups may assist in the process by binding hydrophobic phospholipids in the mitochondrial membrane. The structure of metformin is indicated. MMP, mitochondrial membrane potential. Color images are available online.
FIG. 6.
FIG. 6.
ETC complex I produces ROS in both the forward and reverse directions. (A) During forward electron transfer, CoQ receives electrons from complexes I and II. During this process, electrons leak to produce superoxide from the IF site where NADH is oxidized to NAD+ in complex I. When the Q-binding site (IQ) is blocked, electrons cannot be transferred to CoQ, leak and generate ROS. (B) When the CoQ pool becomes over-reduced into ubiquinol, a high MMP favors the reverse transfer of electrons to complex I. During reverse electron transport, electrons leak from complex I, at either the IF or IQ sites, generating a large amount of superoxide. If the IQ site is blocked during reverse electron transport, CoQ is prevented from transferring electrons back to complex 1, which then reduces ROS production from the Iq site. Rotenone blocks both forward and reverse electron flows, causing both increased and decreased mROS production. Metformin exerts only its inhibitory effect on mROS production by selectively blocking the reverse electron flow. CoQ, coenzyme Q. Color images are available online.
FIG. 7.
FIG. 7.
Proposed model of the mechanisms by which metformin reduces lupus pathogenesis. In the oxidative state presented by immune cells in SLE, enhanced mROS synthesis in neutrophils leads to increased NETosis (1). Oxidized mtDNA produced by NETosis (2) induces pDCs to secrete type I IFN (3). Increased mROS production enhances TCR-induced T cell activation as well as T cell death (4). Metformin has been reported to inhibit the functions of neutrophils, CD4+ T cells, pDCs and B cells in either SLE patients or mouse models of the disease. Only neutrophils and CD4+ T cells present a direct involvement of mROS in their pathogenic phenotypes in SLE. The functions of pDCs and B cells may be inhibited by metformin through mROS-independent pathways, or as a consequence of neutrophils and T cell inhibition, respectively. Alternatively, mROS may contribute to pDC and B cell dysfunction in SLE, and metformin may function through a common mechanism in multiple pathogenic cell types in SLE. TCR, T cell receptor; mtDNA, mitochondrial DNA. Color images are available online.
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References

    1. Almeida A, Almeida J, Bolaños JP, and Moncada S. Different responses of astrocytes and neurons to nitric oxide: the role of glycolytically generated ATP in astrocyte protection. Proc Natl Acad Sci U S A 98: 15294–15299, 2001. - PMC - PubMed
    1. An H, Wei R, Ke J, Yang J, Liu Y, Wang X, Wang G, and Hong T. Metformin attenuates fluctuating glucose-induced endothelial dysfunction through enhancing GTPCH1-mediated eNOS recoupling and inhibiting NADPH oxidase. J Diabetes Complications 30: 1017–1024, 2016. - PubMed
    1. Apostolopoulos D, Vincent F, Hoi A, and Morand E. Associations of metabolic syndrome in SLE. Lupus Sci Med 7: e000436, 2020. - PMC - PubMed
    1. Armstrong DL, Eisenstein M, Zidovetzki R, and Jacob CO. Systemic lupus erythematosus-associated neutrophil cytosolic factor 2 mutation affects the structure of NADPH oxidase complex. J Biol Chem 290: 12595–12602, 2015. - PMC - PubMed
    1. Bagaitkar J, Huang J, Zeng MY, Pech NK, Monlish DA, Perez-Zapata LJ, Miralda I, Schuettpelz LG, and Dinauer MC. NADPH oxidase activation regulates apoptotic neutrophil clearance by murine macrophages. Blood 131: 2367–2378, 2018. - PMC - PubMed

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