Proteostasis and REDOX state in the heart
Laboratory of Cardiac Disease, Redox Signaling and Cell Regeneration, Division of Cardiology, University of Utah School of Medicine, Salt Lake City, USA. AJP Heart and Circulatory Physiology
(Impact Factor: 3.84).
01/2012; 302(1):H24-37. DOI: 10.1152/ajpheart.00903.2011
Force-generating contractile cells of the myocardium must achieve and maintain their primary function as an efficient mechanical pump over the life span of the organism. Because only half of the cardiomyocytes can be replaced during the entire human life span, the maintenance strategy elicited by cardiac cells relies on uninterrupted renewal of their components, including proteins whose specialized functions constitute this complex and sophisticated contractile apparatus. Thus cardiac proteins are continuously synthesized and degraded to ensure proteome homeostasis, also termed "proteostasis." Once synthesized, proteins undergo additional folding, posttranslational modifications, and trafficking and/or become involved in protein-protein or protein-DNA interactions to exert their functions. This includes key transient interactions of cardiac proteins with molecular chaperones, which assist with quality control at multiple levels to prevent misfolding or to facilitate degradation. Importantly, cardiac proteome maintenance depends on the cellular environment and, in particular, the reduction-oxidation (REDOX) state, which is significantly different among cardiac organelles (e.g., mitochondria and endoplasmic reticulum). Taking into account the high metabolic activity for oxygen consumption and ATP production by mitochondria, it is a challenge for cardiac cells to maintain the REDOX state while preventing either excessive oxidative or reductive stress. A perturbed REDOX environment can affect protein handling and conformation (e.g., disulfide bonds), disrupt key structure-function relationships, and trigger a pathogenic cascade of protein aggregation, decreased cell survival, and increased organ dysfunction. This review covers current knowledge regarding the general domain of REDOX state and protein folding, specifically in cardiomyocytes under normal-healthy conditions and during disease states associated with morbidity and mortality in humans.
Available from: Miguel A Aon
- "Keeping a proper cellular/mitochondrial RE is vital for optimal excitation-contraction (EC) coupling as well as energy supply in the heart (Burgoyne et al., 2012; Christians and Benjamin, 2012; Nickel et al., 2013, 2014). Intracellular redox balance affects Ca2+ handling by interfering with a wide range of proteins implicated in EC coupling (Fauconnier et al., 2007) including the SR Ca2+ release channels [the ryanodine receptors], the SR Ca2+ pumps, and the sarcolemmal Na+/Ca2+ exchanger (Zima and Blatter, 2006; Dedkova and Blatter, 2008). "
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ABSTRACT: Current scientific debates center on the impact of lipids and mitochondrial function on diverse aspects of human health, nutrition and disease, among them the association of lipotoxicity with the onset of insulin resistance in skeletal muscle, and with heart dysfunction in obesity and diabetes. Mitochondria play a fundamental role in aging and in prevalent acute or chronic diseases. Lipids are main mitochondrial fuels however these molecules can also behave as uncouplers and inhibitors of oxidative phosphorylation. Knowledge about the functional composition of these contradictory effects and their impact on mitochondrial-cellular energetics/redox status is incomplete. Cells store fatty acids (FAs) as triacylglycerol and package them into cytoplasmic lipid droplets (LDs). New emerging data shows the LD as a highly dynamic storage pool of FAs that can be used for energy reserve. Lipid excess packaging into LDs can be seen as an adaptive response to fulfilling energy supply without hindering mitochondrial or cellular redox status and keeping low concentration of lipotoxic intermediates. Herein we review the mechanisms of action and utilization of lipids by mitochondria reported in liver, heart and skeletal muscle under relevant physiological situations, e.g., exercise. We report on perilipins, a family of proteins that associate with LDs in response to loading of cells with lipids. Evidence showing that in addition to physical contact, mitochondria and LDs exhibit metabolic interactions is presented and discussed. A hypothetical model of channeled lipid utilization by mitochondria is proposed. Direct delivery and channeled processing of lipids in mitochondria could represent a reliable and efficient way to maintain reactive oxygen species (ROS) within levels compatible with signaling while ensuring robust and reliable energy supply.
Frontiers in Physiology 07/2014; 5:282. DOI:10.3389/fphys.2014.00282 · 3.53 Impact Factor
Available from: Miguel A Aon
- "It is now well established that significant perturbations in the mitochondrial redox environment trigger mitochondrial m depolarization that under critical conditions can scale up to the whole heart, thereby producing fatal arrhythmias (Aon et al., 2009; Kembro et al., in press). Reactive oxygen species (ROS) affect cardiac ion channels, cytoplasmic ionic balance, contractile proteins, and EC coupling (Christians and Benjamin, 2012; Aggarwal and Makielski, 2013). In this context, the work of Florea and Blatter poses several key questions worth investigating . "
Frontiers in Physiology 04/2013; 4:83. DOI:10.3389/fphys.2013.00083 · 3.53 Impact Factor
Available from: onlinelibrary.wiley.com
- "An important mediator of this regulation is the transcription factor Nrf2 (nuclear factor E2-related factor 2). Nrf2-regulated genes encode antioxidants, phase-2 detoxification enzymes, mediators of glutathione synthesis, chaperones, and other protective gene products (Sykiotis & Bohmann, 2010). In addition to averting acute oxidative stress, well-controlled redox homeostasis is thought to support a number of critical cellular and organism functions such as signal transduction (Burhans & Heintz, 2009), proteostasis (Balch et al., 2008; Christians & Benjamin, 2011), and stem cell maintenance. Furthermore, recent evidence supports a role of Nrf2 signaling in the control of energy metabolism (reviewed in Sykiotis et al., 2011). "
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ABSTRACT: Aging isa degenerative process characterized by declining molecular, cell and organ functions, and accompanied by the progressive accumulation of oxidatively damaged macromolecules. This increased oxidative damage may be causally related to an age-associateddysfunction of defense mechanisms, which effectively protect young individuals from oxidative insults. Consistently, older organisms are more sensitive to acute oxidative stress exposures than young ones.In studies on the Drosophila Nrf2 transcription factor CncC, we have investigated possiblecausesfor this loss of stress resistance and its connection to the aging process.Nrf2 is amaster regulator of antioxidant and stress defense gene expression with established functions in the control of longevity. Here weshow that the expression of protective Nrf2/CncC target genes in unstressed conditionsdoes not generally decrease in older flies. However, aging flies progressivelylose the ability to activate Nrf2 targets in response to acute stress exposure. We propose that the resulting inability to dynamically adjust the expression of Nrf2 target genes to the organism's internal and external conditions contributes to age-related loss of homeostasis and fitness.In support of this hypothesis, the Drosophila small Maf protein, MafS, an Nrf2 dimerization partner, is critical to maintainresponsiveness of the Nrf2 system: overexpression of MafS in older flies preserves Nrf2/CncCsignaling competence and improvesmeasures of age-associated functional decline.The maintenance of acute stress resistance, motor function, and heart performance in aging flies over expressing MafSsupports a critical role for signal responsiveness of Nrf2 function in promoting youthful phenotypes. © 2013 The Authors Aging Cell © 2013 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.
Aging cell 03/2013; 12(4). DOI:10.1111/acel.12078 · 6.34 Impact Factor
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