Mitochondrial respiratory supercomplex association limits production of reactive oxygen species from complex I.
01 Nov 2013-Antioxidants & Redox Signaling (Mary Ann Liebert, Inc. 140 Huguenot Street, 3rd Floor New Rochelle, NY 10801 USA)-Vol. 19, Iss: 13, pp 1469-1480
TL;DR: The results of this investigation provide experimental evidence that the production of ROS is strongly increased in either model, supporting the view that disruption or prevention of the association between Complex I and Complex III by different means enhances the generation of superoxide from Complex I.
Abstract: Aims: The mitochondrial respiratory chain is recognized today to be arranged in supramolecular assemblies (supercomplexes). Besides conferring a kinetic advantage (substrate channeling) and being required for the assembly and stability of Complex I, indirect considerations support the view that supercomplexes may also prevent excessive formation of reactive oxygen species (ROS) from the respiratory chain. In the present study, we have directly addressed this issue by testing the ROS generation by Complex I in two experimental systems in which the supramolecular organization of the respiratory assemblies is impaired by: (i) treatment either of bovine heart mitochondria or liposome-reconstituted supercomplex I-III with dodecyl maltoside; (ii) reconstitution of Complexes I and III at high phospholipids to protein ratio. Results: The results of our investigation provide experimental evidence that the production of ROS is strongly increased in either model, supporting the view that disruption or preve...
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TL;DR: In this article, insights into the mechanisms of mitochondrial dysfunction in heart failure are presented, along with an overview of emerging treatments with the potential to improve the function of the failing heart by targeting mitochondria.
Abstract: Heart failure is a pressing worldwide public-health problem with millions of patients having worsening heart failure. Despite all the available therapies, the condition carries a very poor prognosis. Existing therapies provide symptomatic and clinical benefit, but do not fully address molecular abnormalities that occur in cardiomyocytes. This shortcoming is particularly important given that most patients with heart failure have viable dysfunctional myocardium, in which an improvement or normalization of function might be possible. Although the pathophysiology of heart failure is complex, mitochondrial dysfunction seems to be an important target for therapy to improve cardiac function directly. Mitochondrial abnormalities include impaired mitochondrial electron transport chain activity, increased formation of reactive oxygen species, shifted metabolic substrate utilization, aberrant mitochondrial dynamics, and altered ion homeostasis. In this Consensus Statement, insights into the mechanisms of mitochondrial dysfunction in heart failure are presented, along with an overview of emerging treatments with the potential to improve the function of the failing heart by targeting mitochondria.
462 citations
TL;DR: SS‐31 represents a new class of compounds that can recharge the cellular powerhouse and restore bioenergetics and provides an update of its clinical development programme.
Abstract: A decline in energy is common in aging, and the restoration of mitochondrial bioenergetics may offer a common approach for the treatment of numerous age-associated diseases. Cardiolipin is a unique phospholipid that is exclusively expressed on the inner mitochondrial membrane where it plays an important structural role in cristae formation and the organization of the respiratory complexes into supercomplexes for optimal oxidative phosphorylation. The interaction between cardiolipin and cytochrome c determines whether cytochrome c acts as an electron carrier or peroxidase. Cardiolipin peroxidation and depletion have been reported in a variety of pathological conditions associated with energy deficiency, and cardiolipin has been identified as a target for drug development. This review focuses on the discovery and development of the first cardiolipin-protective compound as a therapeutic agent. SS-31 is a member of the Szeto-Schiller (SS) peptides known to selectively target the inner mitochondrial membrane. SS-31 binds selectively to cardiolipin via electrostatic and hydrophobic interactions. By interacting with cardiolipin, SS-31 prevents cardiolipin from converting cytochrome c into a peroxidase while protecting its electron carrying function. As a result, SS-31 protects the structure of mitochondrial cristae and promotes oxidative phosphorylation. SS-31 represents a new class of compounds that can recharge the cellular powerhouse and restore bioenergetics. Extensive animal studies have shown that targeting such a fundamental mechanism can benefit highly complex diseases that share a common pathogenesis of bioenergetics failure. This review summarizes the mechanisms of action and therapeutic potential of SS-31 and provides an update of its clinical development programme.
377 citations
Cites background from "Mitochondrial respiratory supercomp..."
...Disruption of supercomplex formation can enhance ROS generation from complex I (Maranzana et al., 2013)....
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TL;DR: These are the first complete architectures of the dominant, physiologically relevant state of the electron transport chain of mammalian (ovine) supercomplexes determined by cryo-electron microscopy.
Abstract: Mitochondrial electron transport chain complexes are organized into supercomplexes responsible for carrying out cellular respiration. Here we present three architectures of mammalian (ovine) supercomplexes determined by cryo-electron microscopy. We identify two distinct arrangements of supercomplex CICIII2CIV (the respirasome)—a major ‘tight’ form and a minor ‘loose’ form (resolved at the resolution of 5.8 A and 6.7 A, respectively), which may represent different stages in supercomplex assembly or disassembly. We have also determined an architecture of supercomplex CICIII2 at 7.8 A resolution. All observed density can be attributed to the known 80 subunits of the individual complexes, including 132 transmembrane helices. The individual complexes form tight interactions that vary between the architectures, with complex IV subunit COX7a switching contact from complex III to complex I. The arrangement of active sites within the supercomplex may help control reactive oxygen species production. To our knowledge, these are the first complete architectures of the dominant, physiologically relevant state of the electron transport chain. Respirasomes are supercomplexes of mitochondrial electron transport chain complexes that are responsible for cellular respiration and energy production; cryo-electron microscopy structures of mammalian (sheep) respirasomes are presented. Mitochondrial electron transport chain complexes are responsible for cellular respiration and energy production. They are organized in supercomplexes called respirasomes. Two studies in this issue of Nature report cryo-electron microscopy structures of the supercomplex consisting of complex I, the dimer of complex III and complex IV at resolutions ranging from 5.4 A to 7.8 A. Maojun Yang and colleagues study the respirasome isolated from porcine heart, whereas Leonid Sazanov and colleagues obtain it from ovine heart. The structures provide insights into the organization of subunits within complexes and the interactions between the complexes.
376 citations
01 May 2014
TL;DR: Evidence supporting the role of mitochondrial oxidative stress, mitochondrial damage and dysfunction in aging and healthspan, including cardiac aging, age-dependent cardiovascular diseases, skeletal muscle aging, neurodegenerative diseases, insulin resistance and diabetes as well as age-related cancers is reviewed.
Abstract: The free radical theory of aging proposes that reactive oxygen species (ROS)-induced accumulation of damage to cellular macromolecules is a primary driving force of aging and a major determinant of lifespan. Although this theory is one of the most popular explanations for the cause of aging, several experimental rodent models of antioxidant manipulation have failed to affect lifespan. Moreover, antioxidant supplementation clinical trials have been largely disappointing. The mitochondrial theory of aging specifies more particularly that mitochondria are both the primary sources of ROS and the primary targets of ROS damage. In addition to effects on lifespan and aging, mitochondrial ROS have been shown to play a central role in healthspan of many vital organ systems. In this article we review the evidence supporting the role of mitochondrial oxidative stress, mitochondrial damage and dysfunction in aging and healthspan, including cardiac aging, age-dependent cardiovascular diseases, skeletal muscle aging, neurodegenerative diseases, insulin resistance and diabetes as well as age-related cancers. The crosstalk of mitochondrial ROS, redox, and other cellular signaling is briefly presented. Potential therapeutic strategies to improve mitochondrial function in aging and healthspan are reviewed, with a focus on mitochondrial protective drugs, such as the mitochondrial antioxidants MitoQ, SkQ1, and the mitochondrial protective peptide SS-31.
369 citations
Cites background from "Mitochondrial respiratory supercomp..."
...Disruption of super complex formation not only reduces oxidative phosphorylation but also increases ROS formation by complex I [205]....
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TL;DR: The potential roles played by oxidative stress and cardiolipin alterations in mitochondrial dysfunction associated with NAFLD are focused on.
Abstract: Nonalcoholic fatty liver disease (NAFLD) is today considered the most common form of chronic liver disease, affecting a high proportion of the population worldwide. NAFLD encompasses a large spectrum of liver damage, ranging from simple steatosis to steatohepatitis, advanced fibrosis and cirrhosis. Obesity, hyperglycemia, type 2 diabetes and hypertriglyceridemia are the most important risk factors. The pathogenesis of NAFLD and its progression to fibrosis and chronic liver disease is still unknown. Accumulating evidence indicates that mitochondrial dysfunction plays a key role in the physiopathology of NAFLD, although the mechanisms underlying this dysfunction are still unclear. Oxidative stress is considered an important factor in producing lethal hepatocyte injury associated with NAFLD. Mitochondrial respiratory chain is the main subcellular source of reactive oxygen species (ROS), which may damage mitochondrial proteins, lipids and mitochondrial DNA. Cardiolipin, a phospholipid located at the level of the inner mitochondrial membrane, plays an important role in several reactions and processes involved in mitochondrial bioenergetics as well as in mitochondrial dependent steps of apoptosis. This phospholipid is particularly susceptible to ROS attack. Cardiolipin peroxidation has been associated with mitochondrial dysfunction in multiple tissues in several physiopathological conditions, including NAFLD. In this review, we focus on the potential roles played by oxidative stress and cardiolipin alterations in mitochondrial dysfunction associated with NAFLD.
321 citations
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Abstract: Summary
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