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Review
. 2020 Jul 14:11:755.
doi: 10.3389/fphys.2020.00755. eCollection 2020.

Manganese Superoxide Dismutase Dysfunction and the Pathogenesis of Kidney Disease

Munehiro Kitada  1   2 , Jing Xu  1 , Yoshio Ogura  1 , Itaru Monno  1 , Daisuke Koya  1   2
Affiliations
Review

Manganese Superoxide Dismutase Dysfunction and the Pathogenesis of Kidney Disease

Munehiro Kitada et al. Front Physiol. .

Abstract

The mitochondria are a major source of reactive oxygen species (ROS). Superoxide anion (O2 •-) is produced by the process of oxidative phosphorylation associated with glucose, amino acid, and fatty acid metabolism, resulting in the production of adenosine triphosphate (ATP) in the mitochondria. Excess production of reactive oxidants in the mitochondria, including O2 •-, and its by-product, peroxynitrite (ONOO-), which is generated by a reaction between O2 •- with nitric oxide (NO•), alters cellular function via oxidative modification of proteins, lipids, and nucleic acids. Mitochondria maintain an antioxidant enzyme system that eliminates excess ROS; manganese superoxide dismutase (Mn-SOD) is one of the major components of this system, as it catalyzes the first step involved in scavenging ROS. Reduced expression and/or the activity of Mn-SOD results in diminished mitochondrial antioxidant capacity; this can impair the overall health of the cell by altering mitochondrial function and may lead to the development and progression of kidney disease. Targeted therapeutic agents may protect mitochondrial proteins, including Mn-SOD against oxidative stress-induced dysfunction, and this may consequently lead to the protection of renal function. Here, we describe the biological function and regulation of Mn-SOD and review the significance of mitochondrial oxidative stress concerning the pathogenesis of kidney diseases, including chronic kidney disease (CKD) and acute kidney injury (AKI), with a focus on Mn-SOD dysfunction.

Keywords: acute kidney injury; chronic kidney disease; manganese superoxide dismutase; mitochondria; peroxynitrite; posttranslational modification.

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Figures

FIGURE 1
FIGURE 1
Function of manganese superoxide dismutase (Mn-SOD). Superoxide (O2•–) is produced by the electron transport chain (ETC) during nutrient metabolism by the tricarboxylic acid (TCA) cycle. Mn-SOD is localized in the mitochondrial matrix, where it catalyzes the dismutation of O2•– to H2O2. By contrast, Cu/Zn-SOD, which is located in the inner membrane space of mitochondria, catalyzes the conversion of O2•– to hydrogen peroxide (H2O2). H2O2 is further metabolized by the glutathione peroxidase (GPx) and the peroxiredoxin (PRx)/thioredoxin (TRx) system in mitochondrial matrix or by catalase (CAT) GPx and PRx/TRx in the cytosol. O2•– and nitric oxide (NO•) can react to form peroxynitrite (ONOO–), giving rise to nitrogen dioxide (NO2•) and hydroxyl radical (OH•); eventually, stable nitrite (NO3–) is produced. H2O2 is converted to OH via the Fenton/Haber–Weiss reaction. O2•– can reduce ferric iron (Fe3+) to ferrous iron (Fe2+) in iron–sulfur centers of proteins, ultimately resulting in the production of H2O2. Moreover, the protonation of O2•– generates the hydroperoxyl radical, HO2.
FIGURE 2
FIGURE 2
Regulation of manganese superoxide dismutase (Mn-SOD) enzyme activity by translational modifications. ONOO– promotes Mn-SOD inactivation by nitrating the critical Tyr34 at the enzyme active site. Acetylation of Mn-SOD at K68, K122, K53, and K89 residues also induces Mn-SOD inactivation. Reduced levels of ONOO– and activation of NAD-dependent deacetylase sirtuin-3 (SIRT3) lead to Mn-SOD reactivation through denitrification or deacetylation of the target residues.
FIGURE 3
FIGURE 3
Mitochondrial oxidative, manganese superoxide dismutase (Mn-SOD) dysfunction, and kidney disease. Mitochondrial oxidative stress associated with Mn-SOD dysfunction in the kidney is one of the key factors underlying the pathogenesis of kidney disease, including acute kidney injury (AKI), chronic kidney disease (CKD), as well as the AKI to CKD transition through glomerular and tubulointerstitial fibrosis, inflammation, excessive apoptosis of renal cells, and tubular cell damage. Several mitochondria-targeted drugs may improve the kidney disease through the improvement of mitochondrial oxidative stress. I/R, Ischemia/reperfusion; DKD, diabetic kidney disease; HT, hypertension; UUO, unilateral ureteral obstruction.
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