Superoxide Dismutase, Mitochondrial Dysfunction, and Neurodegenerative Diseases

Authored by: Jahaun Azadmanesh , Gloria E. O. Borgstahl

Handbook of Mitochondrial Dysfunction

Print publication date:  June  2019
Online publication date:  May  2019

Print ISBN: 9781138336087
eBook ISBN: 9780429443336
Adobe ISBN:

10.1201/9780429443336-16

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Abstract

Excessive amounts of reactive oxygen/nitrogen species (ROS/RNS), e.g. hydroxyl radical (OH) and peroxynitrite (ONOO), wreak oxidative havoc in cells by causing DNA strand breaks, crosslinking or fragmentation of proteins and peroxidation of lipids. Oxidation is especially damaging to mitochondria, the source of energy for cells. Interestingly, mitochondria are also the largest source of ROS/RNS in cells. Superoxide (O2 •–), produced as a byproduct to energy production by the mitochondrial electron transport chain (ETC), is capable of directly damaging the mitochondria, and also serves as a precursor to more powerful ROS and RNS, such as OH and ONOO. Superoxide dismutases (SODs) are the first line of defense in combating this oxidative damage by converting O2 •– into oxygen (O2) and hydrogen peroxide (H2O2). Manganese SOD (MnSOD) resides within the mitochondrial matrix while intracellular copper-zinc SOD (CuZnSOD) resides in the mitochondrial intermembrane space (MIMS) and cytosol. The enzymatic function of these SODs is paramount to preserving the mitochondria and its energy production. Despite their biological importance, the enzymatic mechanism of SODs is still unclear. SODs perform their function through highly efficient proton-coupled electron transfers (PCETs) that are extremely difficult to detect. Dysfunction of either MnSOD or CuZnSOD can lead to mitochondrial degeneration, a characteristic of neurodegenerative pathologies such as Alzheimer’s disease (AD), Parkinson’s disease and amyotrophic lateral sclerosis (ALS). Here, we review the mitochondrial damage caused by ROS/RNS, current insights into the mysterious catalytic mechanism of SODs, and how neurodegenerative pathologies develop when SODs become dysfunctional.

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