Targeting mitochondrial oxidative stress with MitoQ reduces NET formation and kidney disease in lupus-prone MRL-lprmice

Abstract

ObjectivesRecent investigations in humans and mouse models with lupus have revealed evidence of mitochondrial dysfunction and production of mitochondrial reactive oxygen species (mROS) in T cells and neutrophils. This can provoke numerous cellular changes including oxidation of nucleic acids, proteins, lipids and even induction of cell death. We have previously observed that in T cells from patients with lupus, the increased mROS is capable of provoking oligomerisation of mitochondrial antiviral stimulator (MAVS) and production of type I interferon (IFN-I). mROS in SLE neutrophils also promotes the formation of neutrophil extracellular traps (NETs), which are increased in lupus and implicated in renal damage. As a result, in addition to traditional immunosuppression, more comprehensive treatments for lupus may also include non-immune therapy, such as antioxidants.MethodsLupus-prone MRL-lpr mice were treated from weaning for 11 weeks with the mitochondria-targeted antioxidant, MitoQ (200 µM) in drinking water. Mice were then assessed for ROS production in neutrophils, NET formation, MAVS oligomerisation, serum IFN-I, autoantibody production and renal function.ResultsMitoQ-treated mice manifested reduced neutrophil ROS and NET formation, decreased MAVS oligomerisation and serum IFN-I, and reduced immune complex formation in kidneys, despite no change in serum autoantibody .ConclusionsThese findings reveal the potential utility of targeting mROS in addition to traditional immunosuppressive therapy for lupus.

NETosis: Molecular Mechanisms, Role in Physiology and Pathology

“…One of the peculiarities of low-density granulocytes is the increased production of mitochondrial ROS. Recently, it was shown that the mitochondria-targeted antioxidant MitoQ (similar in structure to SkQ1) suppressed NETs accumulation and pathological manifestations in the mouse model of systemic lupus erythematosus [ 102 ].…”

“…In the mouse model of systemic inflammatory syndrome, SkQ1 prevented lethal effect of the inflammatory cytokine TNF [ 111 ]. The antioxidant MitoQ, similar in structure to SkQ1, suppressed NETosis in the mouse model of systemic lupus erythematosus [ 102 ]. These results suggest, that drugs based on mitochondria-targeted antioxidants will be created soon in order to treat diseases associated with the excessive NETosis, and, in particular, to combat COVID-19.…”

Do free radical NETwork and oxidative stress disparities in African Americans enhance their vulnerability to SARS-CoV-2 infection and COVID-19 severity?

“…Whether SLE-induced NETs are mediated by O 2 •– /H 2 O 2 -independent hyper-citrullination or Nox2-or mitochondria-dependent oxidants remains debatable; however, reports suggest that mitochondria-targeted antioxidants (Mito-Quinone [Mito-Q] and Mito-TEMPOL) attenuated the severity of lupus in the mouse model [ 86 , 87 ]. It was suggested that Mito-Q could inhibit type 1 interferon (IFN-1), upstream of O 2 •– production [ 88 ]. Mito-Q also inhibited IFN-1 that is a byproduct of NETosis [ 88 ].…”

“…It was suggested that Mito-Q could inhibit type 1 interferon (IFN-1), upstream of O 2 •– production [ 88 ]. Mito-Q also inhibited IFN-1 that is a byproduct of NETosis [ 88 ]. Immune system activation by mitochondria was recently reported [ 89 ].…”

“…Mito-apocynin synthesized from apocynin, a non-specific inhibitor of Nox2, inhibited Nox2 and oxidative/nitrative modification of proteins and inflammation in microglia [ 145 ]. Mito-Q, co-enzyme Q conjugated to the triphenylphosphonium moiety, decreased NET formation in a lupus mouse model [ 88 ]. Mito-Q treatment of SARS-CoV-2-infected monocytes from diabetics decreased viral replication and cytokine upregulation [ 79 ].…”