- Please check and comment entries here.
Oxidative Stress and Mitochondrial Dysfunction
Since impaired mitochondria are a major source of reactive oxygen species (ROS), oxidative stress is closely linked to mitochondrial dysfunction and has been assumed to be the principal molecular mechanism for the pathogenesis of various diseases, especially neurodegenerative disorders. Molecular imaging reflecting oxidative stress has improved our insights into the pathological mechanisms of diseases associated with mitochondrial dysfunction, and is a promising tool for monitoring further antioxidant therapies.
1. Oxidative Stress Caused by Reactive Oxygen Species
Oxidative stress is classically defined as an imbalanced redox state in which the oxidation effect caused by increased production of reactive oxygen species (ROS) exceeds the defense capacity of the antioxidant mechanism . Enhanced oxidative stress due to excess ROS generation leads to oxidative damage to the cellular components, such as proteins, lipids, and DNA. Additionally, ROS change the expression of nuclear factor kappa B (NF-κB), a transcription factor responsible for inducing inflammation and apoptosis . These ROS-induced pathological mechanisms provoke tissue and organ dysfunction, especially neuronal degeneration in the brain . ROS such as superoxide (O2−), hydroxyl radical (OH), and hydrogen peroxide (H2O2), are derived from molecular oxygen by the reduction. In particular, superoxide and hydroxyl radical are classified as free radicals, which show high chemical reactivity due to their unpaired electrons . ROS are endogenously produced in the mitochondria, peroxisomes, and endoplasmic reticulum of cells . Among these organelles, mitochondria, which consume more than 90% of intravital oxygen during oxidative phosphorylation (i.e., the aerobic metabolism), are regarded as the principal endogenous source of ROS . However, under a healthy condition with normal mitochondrial function, the amount of ROS leakage is so small that it can be eliminated by the endogenous biological antioxidants, such as superoxide dismutase (SOD) and glutathione (GSH) .
2. Mitochondria as a Major Source of Reactive Oxygen Species
The mitochondrion is an organelle that produces adenosine triphosphate (ATP) as energy essential for life activities using the intrinsic respiratory chains. In the mitochondrial respiratory chains (a.k.a. electron transport chains), which consist of five complexes (i.e., complex I-V), electrons obtained as the reduced form of nicotinamide adenine dinucleotide (NADH) from the metabolism of glucose (i.e., glycolysis), free fatty acids (i.e., β-oxidation), and the tricarboxylic acid cycle are transported to synthesize ATP . Most of the transferred electrons are ultimately captured by oxygen in the four-electron reduction whereby electrons and oxygen are detoxified to harmless and stable water molecules . However, in respiratory chain impairment due to mitochondrial dysfunction, deteriorated electron transport provokes excessive accumulation of electrons relative to the amount of oxygen, resulting in an over-reductive state . Because ROS are produced by the reduction of molecular oxygen, redundant electrons that leak from the impaired respiratory chains in an over-reductive state readily react with oxygen, which generates ROS . A total of nine sites have been identified as the sources of mitochondrial ROS; complex I produces superoxide solely in the matrix, while complex III generates superoxide in both the matrix and the intermembrane space . As explained above, mitochondrial respiratory chain impairment provokes an over-reductive state, and this state under the normoxic condition results in oxidative stress, which suggests that the evaluation of an over-reductive state using molecular imaging would be a promising marker for oxidative stress .
3. Oxidative Stress Based on Mitochondrial Dysfunction in Neurodegenerative Disorders
As mentioned above, mitochondrial respiratory chain impairment causes oxidative stress due to an over-reductive state, in addition to an ATP production deficit . Since mitochondria are distributed throughout the body, mitochondrial dysfunction may cause failures of various organs. In particular, the brain consumes 20% of intravital oxygen and has a relatively fragile antioxidant capacity , which underlies the vulnerability of the neurons and glial cells to oxidative stress due to mitochondrial dysfunction . Besides reduced respiratory capacity of mitochondria, there are other possible causes of oxidative stress in the brain, e.g., neuroinflammation, protein aggregation, and decreased antioxidant defenses . Aging is also a major factor in promoting these pathological mechanisms, especially decreased mitochondrial function and antioxidant potential, leading to the enhancement of cerebral oxidative stress in elderly people . These factors explain why the prevalence of neurodegenerative disorders increases with advancing age, and many pathological and biochemical studies have demonstrated enhanced oxidative stress in various neurodegenerative disorders . Interestingly, basic studies showed that aggregated misfolded proteins induce mitochondrial dysfunction and ROS generation . Conversely, ROS may facilitate neurotoxic protein aggregation, such as amyloid-β (in Alzheimer's disease), α-synuclein (in Parkinson’s disease), and SOD1 (in amyotrophic lateral sclerosis (ALS)), as well as mitochondrial impairment, producing a vicious cycle among oxidative stress, mitochondrial dysfunction and protein aggregation . These findings may indicate that the increase in ROS production precedes the appearance of plaque deposits and that mitochondrial dysfunction can be an early event that precedes protein aggregation in neurodegenerative disorders. . Recent studies with positron emission tomography (PET) delineated enhancement of oxidative stress in brain regions of pathologically responsible sites of neurodegeneration in living patients, i.e., the stroke-like lesions of mitochondrial disease (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes: MELAS), the striatum of Parkinson’s disease, and the motor and motor-related cortices of ALS, suggesting that oxidative stress based on mitochondrial dysfunction is closely associated with the neurodegenerative process in these diseases . PET imaging for oxidative stress improves our insight into the pathogenesis of neurodegenerative disorders, and is a promising tool for monitoring further antioxidant and mitochondrial therapies .
This entry is adapted from 10.3390/antiox9090861
- Kalavathi Dasuri; Le Zhang; Jeffrey N. Keller; Oxidative stress, neurodegeneration, and the balance of protein degradation and protein synthesis. Free Radical Biology and Medicine 2013, 62, 170-185, 10.1016/j.freeradbiomed.2012.09.016.
- C Bubici; S Papa; K Dean; G Franzoso; Mutual cross-talk between reactive oxygen species and nuclear factor-kappa B: molecular basis and biological significance. Oncogene 2006, 25, 6731-6748, 10.1038/sj.onc.1209936.
- Sonia Gandhi; Andrey Y. Abramov; Mechanism of Oxidative Stress in Neurodegeneration. Oxidative Medicine and Cellular Longevity 2012, 2012, 1-11, 10.1155/2012/428010.
- David A. Patten; Marc Germain; Melissa A. Kelly; Ruth S Slack; Reactive Oxygen Species: Stuck in the Middle of Neurodegeneration. Journal of Alzheimer's Disease 2010, 20, S357-S367, 10.3233/jad-2010-100498.
- Subhashini Bolisetty; Edgar A. Jaimes; Mitochondria and Reactive Oxygen Species: Physiology and Pathophysiology. International Journal of Molecular Sciences 2013, 14, 6306-6344, 10.3390/ijms14036306.
- Florian L. Muller; The nature and mechanism of superoxide production by the electron transport chain: Its relevance to aging. AGE 2000, 23, 227-253, 10.1007/s11357-000-0022-9.
- Giorgio Lenaz; Role of mitochondria in oxidative stress and ageing. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1998, 1366, 53-67, 10.1016/s0005-2728(98)00120-0.
- Raynoo Thanan; Shinji Oikawa; Yusuke Hiraku; Shiho Ohnishi; Ning Ma; Somchai Pinlaor; Puangrat Yongvanit; Shosuke Kawanishi; Mariko Murata; Oxidative Stress and Its Significant Roles in Neurodegenerative Diseases and Cancer. International Journal of Molecular Sciences 2014, 16, 193-217, 10.3390/ijms16010193.
- Sten Orrenius; Reactive Oxygen Species in Mitochondria-Mediated Cell Death. Drug Metabolism Reviews 2007, 39, 443-455, 10.1080/03602530701468516.
- Masamichi Ikawa; Yasuyuki Kawai; Kenichiro Arakawa; Tatsuro Tsuchida; Isamu Miyamori; Masaru Kuriyama; Masashi Tanaka; Makoto Yoneda; Evaluation of respiratory chain failure in mitochondrial cardiomyopathy by assessments of 99mTc-MIBI washout and 123I-BMIPP/99mTc-MIBI mismatch. Mitochondrion 2007, 7, 164-170, 10.1016/j.mito.2006.11.008.
- Masamichi Ikawa; Makoto Yoneda; Masashi Tanaka; Energy States in Mitochondrial Cardiomyopathy. Circulation Journal 2010, 74, 2560-2561, 10.1253/circj.cj-10-1062.
- Julio F Turrens; Mitochondrial formation of reactive oxygen species. The Journal of Physiology 2003, 552, 335-344, 10.1111/j.1469-7793.2003.00335.x.
- Kenjiro Kami; Yasunori Fujita; Saori Igarashi; Sayaka Koike; Shoko Sugawara; Satsuki Ikeda; Naomi Sato; Masafumi Ito; Masashi Tanaka; Masaru Tomita; et al. Metabolomic profiling rationalized pyruvate efficacy in cybrid cells harboring MELAS mitochondrial DNA mutations. Mitochondrion 2012, 12, 644-653, 10.1016/j.mito.2012.07.113.
- Yukie Yoshii; Makoto Yoneda; Masamichi Ikawa; Takako Furukawa; Yasushi Kiyono; Tetsuya Mori; Hiroshi Yoshii; Nobuyuki Oyama; Hidehiko Okazawa; Tsuneo Saga; et al. Radiolabeled Cu-ATSM as a novel indicator of overreduced intracellular state due to mitochondrial dysfunction: studies with mitochondrial DNA-less ρ0 cells and cybrids carrying MELAS mitochondrial DNA mutation. Nuclear Medicine and Biology 2012, 39, 177-185, 10.1016/j.nucmedbio.2011.08.008.
- Hiroko P. Indo; Mercy Davidson; Hsiu-Chuan Yen; Shigeaki Suenaga; Kazuo Tomita; Takeshi Nishii; Masahiro Higuchi; Yasutoshi Koga; Toshihiko Ozawa; Hideyuki J. Majima; et al. Evidence of ROS generation by mitochondria in cells with impaired electron transport chain and mitochondrial DNA damage. Mitochondrion 2007, 7, 106-118, 10.1016/j.mito.2006.11.026.
- Michael P. Murphy; How mitochondria produce reactive oxygen species. Biochemical Journal 2008, 417, 1-13, 10.1042/bj20081386.
- Florian L. Muller; Yuhong Liu; Holly Van Remmen; Complex III Releases Superoxide to Both Sides of the Inner Mitochondrial Membrane. Journal of Biological Chemistry 2004, 279, 49064-49073, 10.1074/jbc.m407715200.
- Masamichi Ikawa; Hidehiko Okazawa; Takashi Kudo; Masaru Kuriyama; Yasuhisa Fujibayashi; Makoto Yoneda; Evaluation of striatal oxidative stress in patients with Parkinson's disease using [62Cu]ATSM PET. Nuclear Medicine and Biology 2011, 38, 945-951, 10.1016/j.nucmedbio.2011.02.016.
- Masamichi Ikawa; Hidehiko Okazawa; Tetsuya Tsujikawa; Akiko Matsunaga; Osamu Yamamura; Tetsuya Mori; Tadanori Hamano; Yasushi Kiyono; Yasunari Nakamoto; Makoto Yoneda; et al. Increased oxidative stress is related to disease severity in the ALS motor cortex: A PET study. Neurology 2015, 84, 2033-2039, 10.1212/wnl.0000000000001588.
- Hidehiko Okazawa; M Ikawa; T Tsujikawa; Y Kiyono; M Yoneda; Brain imaging for oxidative stress and mitochondrial dysfunction in neurodegenerative diseases.. The Quarterly Journal of Nuclear Medicine and Molecular Imaging 2014, 58, 387-397, .
- Robert A Floyd; Antioxidants, Oxidative Stress, and Degenerative Neurological Disorders. Proceedings of the Society for Experimental Biology and Medicine 1999, 222, 236-245, 10.1046/j.1525-1373.1999.d01-140.x.
- Xinkun Wang; Selective neuronal vulnerability to oxidative stress in the brain. Frontiers in Aging Neuroscience 2010, 2, 12, 10.3389/fnagi.2010.00012.
- Miriam Valera-Alberni; Carles Canto; Mitochondrial stress management: a dynamic journey. Cell Stress 2018, 2, 253-274, 10.15698/cst2018.10.158.
- Dominic S. A. Simpson; Peter L. Oliver; ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease. Antioxidants 2020, 9, 743, 10.3390/antiox9080743.
- Giorgio Lenaz; Carla Bovina; Marilena D'aurelio; Romana Fato; Gabriella Formiggini; Maria Luisa Genova; Giovanni Giuliano; Milena Merlo Pich; Ugo Paolucci; Giovanna Parenti Castelli; et al. Role of mitochondria in oxidative stress and aging.. Annals of the New York Academy of Sciences 2002, 959, 199-213, 10.1111/j.1749-6632.2002.tb02094.x.
- Michael T. Lin; M. Flint Beal; Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 2006, 443, 787-795, 10.1038/nature05292.
- Geon Ha Kim; Jieun E. Kim; Sandy Jeong Rhie; Sujung Yoon; The Role of Oxidative Stress in Neurodegenerative Diseases. Experimental Neurobiology 2015, 24, 325-340, 10.5607/en.2015.24.4.325.
- Andrey Y. Abramov; Alexey V. Berezhnov; Evgeniya I. Fedotova; V. P. Zinchenko; Ludmila P. Dolgacheva; Interaction of misfolded proteins and mitochondria in neurodegenerative disorders. Biochemical Society Transactions 2017, 45, 1025-1033, 10.1042/bst20170024.
- Giovanna Cenini; Ana Lloret; Roberta Cascella; Oxidative Stress in Neurodegenerative Diseases: From a Mitochondrial Point of View. Oxidative Medicine and Cellular Longevity 2019, 2019, 1-18, 10.1155/2019/2105607.
- B.J. Tabner; O.M.A. El-Agnaf; M.J. German; N.J. Fullwood; D. Allsop; Protein aggregation, metals and oxidative stress in neurodegenerative diseases. Biochemical Society Transactions 2005, 33, 1082-1086, 10.1042/bst0331082.
- Elise Lévy; Nadine El Banna; Dorothée Baïlle; Amélie Heneman-Masurel; Sandrine Truchet; Human Rezaei; Meng-Er Huang; Vincent Béringue; Davy Martin; Laurence Vernis; et al. Causative Links between Protein Aggregation and Oxidative Stress: A Review. International Journal of Molecular Sciences 2019, 20, 3896, 10.3390/ijms20163896.
- Jia Yao; Ronald W. Irwin; Liqin Zhao; Jon Nilsen; Ryan T. Hamilton; Roberta Diaz Brinton; Mitochondrial bioenergetic deficit precedes Alzheimer's pathology in female mouse model of Alzheimer's disease. Proceedings of the National Academy of Sciences 2009, 106, 14670-14675, 10.1073/pnas.0903563106.
- Elena Radi; Patrizia Formichi; Carla Battisti; Antonio Federico; Apoptosis and Oxidative Stress in Neurodegenerative Diseases. Journal of Alzheimer's Disease 2014, 42, S125-S152, 10.3233/jad-132738.
- Masamichi Ikawa; Hidehiko Okazawa; Kenichiro Arakawa; Takashi Kudo; Hirohiko Kimura; Yasuhisa Fujibayashi; Masaru Kuriyama; Makoto Yoneda; PET imaging of redox and energy states in stroke-like episodes of MELAS. Mitochondrion 2009, 9, 144-148, 10.1016/j.mito.2009.01.011.
- Masamichi Ikawa; Hidehiko Okazawa; Yasunari Nakamoto; Makoto Yoneda; PET Imaging for Oxidative Stress in Neurodegenerative Disorders Associated with Mitochondrial Dysfunction. Antioxidants 2020, 9, 861, 10.3390/antiox9090861.