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Review
. 2015 Jan;56(1):1-7.
doi: 10.3164/jcbn.14-42. Epub 2014 Dec 23.

A mitochondrial superoxide theory for oxidative stress diseases and aging

Hiroko P Indo  1 , Hsiu-Chuan Yen  2 , Ikuo Nakanishi  3 , Ken-Ichiro Matsumoto  3 , Masato Tamura  4 , Yumiko Nagano  4 , Hirofumi Matsui  4 , Oleg Gusev  5 , Richard Cornette  6 , Takashi Okuda  6 , Yukiko Minamiyama  7 , Hiroshi Ichikawa  8 , Shigeaki Suenaga  9 , Misato Oki  10 , Tsuyoshi Sato  9 , Toshihiko Ozawa  11 , Daret K St Clair  12 , Hideyuki J Majima  13
Affiliations
Review

A mitochondrial superoxide theory for oxidative stress diseases and aging

Hiroko P Indo et al. J Clin Biochem Nutr. 2015 Jan.

Abstract

Fridovich identified CuZnSOD in 1969 and manganese superoxide dismutase (MnSOD) in 1973, and proposed "the Superoxide Theory," which postulates that superoxide (O2 (•-)) is the origin of most reactive oxygen species (ROS) and that it undergoes a chain reaction in a cell, playing a central role in the ROS producing system. Increased oxidative stress on an organism causes damage to cells, the smallest constituent unit of an organism, which can lead to the onset of a variety of chronic diseases, such as Alzheimer's, Parkinson's, amyotrophic lateral sclerosis and other neurological diseases caused by abnormalities in biological defenses or increased intracellular reactive oxygen levels. Oxidative stress also plays a role in aging. Antioxidant systems, including non-enzyme low-molecular-weight antioxidants (such as, vitamins A, C and E, polyphenols, glutathione, and coenzyme Q10) and antioxidant enzymes, fight against oxidants in cells. Superoxide is considered to be a major factor in oxidant toxicity, and mitochondrial MnSOD enzymes constitute an essential defense against superoxide. Mitochondria are the major source of superoxide. The reaction of superoxide generated from mitochondria with nitric oxide is faster than SOD catalyzed reaction, and produces peroxynitrite. Thus, based on research conducted after Fridovich's seminal studies, we now propose a modified superoxide theory; i.e., superoxide is the origin of reactive oxygen and nitrogen species (RONS) and, as such, causes various redox related diseases and aging.

Keywords: MnSOD; ROS; mitochondria; oxidative stress diseases and aging; superoxide theory.

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Figures

Fig. 1
Fig. 1
Intracellular antioxidant enzymes and their chain reactions. Superoxide (O2•−), predominantly induced from the mitochondrial electron transport chain (ETC), reacts with nitric oxide (NO•) and forms peroxynitrite (ONOO−). Peroxynitrite, a potent oxidant, then induces apoptosis or necrosis. MnSOD, which locates in mitochondria, eliminates O2•− and inhibits binding with NO•.
Fig. 2
Fig. 2
Formation of peroxynitrite (ONOO−) and its further reactions. Nitrates and/or hydroxylates of proteins, lipids and DNAs, by formation of NO2• and HO• (adapted from Beckman, et al.(8)).
Fig. 3
Fig. 3
MnSOD has a mitochondria targeting signal (MTS). The sequence consists of an alternating pattern (amphipathic helix) composed of 24 amino acids, which includes three positively charged peptides (arginine [R]).
Fig. 4
Fig. 4
A Mitochondrial Superoxide Theory. The binding reaction of superoxide (O2•−) and nitric oxide (NO•) forms peroxynitrite (ONOO−) (amendment to Motoori, et al.(71)).
Fig. 5
Fig. 5
Ultrastructural analysis of cells cultured at pH 8.3 for 6 h. Electron microscopy of (a) SOD transfected cells that appear normal with normal mitochondria (arrow) and (b) NEO cells show accumulation of lysosomes with membrane debris observed internally (arrow). The cell surface demonstrates prominent membrane blebs (arrowhead). Mitochondria show focal swelling and loss of cristae. Focal condensation of chromosomal material is present. This research was originally published in J Biol Chem., Majima HJ, Oberley TD, Furukawa K, Mattson MP, Yen H-C, Szweda LI, St Clair DK: Prevention of mitochondrial injury by manganese superoxide dismutase reveals a primary mechanism for alkaline-induced cell death. J Biol Chem 1998; 273: 8217–8224. Reprint from ref. 9 with permission.
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