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Age-Related Decrease in the Mitochondrial Sirtuin Deacetylase Sirt3 Expression Associated with ROS Accumulation in the Auditory Cortex of the Mimetic Aging Rat Model  [PDF]
Lingling Zeng, Yang Yang, Yujuan Hu, Yu Sun, Zhengde Du, Zhen Xie, Tao Zhou, Weijia Kong
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0088019
Abstract: Age-related dysfunction of the central auditory system, also known as central presbycusis, can affect speech perception and sound localization. Understanding the pathogenesis of central presbycusis will help to develop novel approaches to prevent or treat this disease. In this study, the mechanisms of central presbycusis were investigated using a mimetic aging rat model induced by chronic injection of D-galactose (D-Gal). We showed that malondialdehyde (MDA) levels were increased and manganese superoxide dismutase (SOD2) activity was reduced in the auditory cortex in natural aging and D-Gal-induced mimetic aging rats. Furthermore, mitochondrial DNA (mtDNA) 4834 bp deletion, abnormal ultrastructure and cell apoptosis in the auditory cortex were also found in natural aging and D-Gal mimetic aging rats. Sirt3, a mitochondrial NAD+-dependent deacetylase, has been shown to play a crucial role in controlling cellular reactive oxygen species (ROS) homeostasis. However, the role of Sirt3 in the pathogenesis of age-related central auditory cortex deterioration is still unclear. Here, we showed that decreased Sirt3 expression might be associated with increased SOD2 acetylation, which negatively regulates SOD2 activity. Oxidative stress accumulation was likely the result of low SOD2 activity and a decline in ROS clearance. Our findings indicate that Sirt3 might play an essential role, via the mediation of SOD2, in central presbycusis and that manipulation of Sirt3 expression might provide a new approach to combat aging and oxidative stress-related diseases.
Oxidative Stress, Mitochondrial Dysfunction, and Aging  [PDF]
Hang Cui,Yahui Kong,Hong Zhang
Journal of Signal Transduction , 2012, DOI: 10.1155/2012/646354
Abstract: Aging is an intricate phenomenon characterized by progressive decline in physiological functions and increase in mortality that is often accompanied by many pathological diseases. Although aging is almost universally conserved among all organisms, the underlying molecular mechanisms of aging remain largely elusive. Many theories of aging have been proposed, including the free-radical and mitochondrial theories of aging. Both theories speculate that cumulative damage to mitochondria and mitochondrial DNA (mtDNA) caused by reactive oxygen species (ROS) is one of the causes of aging. Oxidative damage affects replication and transcription of mtDNA and results in a decline in mitochondrial function which in turn leads to enhanced ROS production and further damage to mtDNA. In this paper, we will present the current understanding of the interplay between ROS and mitochondria and will discuss their potential impact on aging and age-related diseases. 1. Introduction The fundamental manifestation of the aging process is a progressive decline in the functional maintenance of tissue homeostasis and an increasing propensity to degenerative diseases and death [1]. It has attracted significant interest to study the underlying mechanisms of aging, and many theories have been put forward to explain the phenomenon of aging. There is an emerging consensus that aging is a multifactorial process, which is genetically determined and influenced epigenetically by environment [2]. Most aging theories postulate a single physiological cause of aging, and likely these theories are correct to a certain degree and in certain aspects of aging. Reactive oxygen species (ROS) are highly reactive molecules that consist of a number of diverse chemical species including superoxide anion ( O 2 ? ), hydroxyl radical ( ? O H ), and hydrogen peroxide (H2O2). Because of their potential to cause oxidative deterioration of DNA, protein, and lipid, ROS have been implicated as one of the causative factors of aging [3]. As ROS are generated mainly as by-products of mitochondrial respiration, mitochondria are thought to be the primary target of oxidative damage and play an important role in aging. Emerging evidence has linked mitochondrial dysfunction to a variety of age-related diseases, including neurodegenerative diseases and cancer. Details of the precise relationship between ROS-induced damage, mitochondrial dysfunction, and aging remain to be elucidated. 2. ROS and Aging 2.1. ROS, Oxidative Damage, and Cellular Signaling There are several sources of ROS within a cell. ROS are generated as
The Role of Mitochondrial DNA Mutations in Mammalian Aging  [PDF]
Gregory C Kujoth,Patrick C Bradshaw,Suraiya Haroon,Tomas A Prolla
PLOS Genetics , 2007, DOI: 10.1371/journal.pgen.0030024
Abstract: Mitochondrial DNA (mtDNA) accumulates both base-substitution mutations and deletions with aging in several tissues in mammals. Here, we examine the evidence supporting a causative role for mtDNA mutations in mammalian aging. We describe and compare human diseases and mouse models associated with mitochondrial genome instability. We also discuss potential mechanisms for the generation of these mutations and the means by which they may mediate their pathological consequences. Strategies for slowing the accumulation and attenuating the effects of mtDNA mutations are discussed.
Mitochondrial Diseases  [cached]
Filiz Koc,Yakup Sarica,Deniz Yerdelen
Arsiv Kaynak Tarama Dergisi , 2003,
Abstract: The oxidative phosphorilasyon (OXPHOS) diseases are heterogeneous group of diseases that are caused by mutations in mitochondrial DNA (mtDNA) or nuclear DNA. These progressive diseases ,often present in early adult life, are characterised by multiorgan involvement and this condition can make diagnosis diffucult. [Archives Medical Review Journal 2003; 12(0.100): 32-80]
The Importance of Mitochondrial DNA in Aging and Cancer  [PDF]
Claus Desler,Maiken Lise Marcker,Keshav K. Singh,Lene Juel Rasmussen
Journal of Aging Research , 2011, DOI: 10.4061/2011/407536
Abstract: Mitochondrial dysfunction has been implicated in premature aging, age-related diseases, and tumor initiation and progression. Alterations of the mitochondrial genome accumulate both in aging tissue and tumors. This paper describes our contemporary view of mechanisms by which alterations of the mitochondrial genome contributes to the development of age- and tumor-related pathological conditions. The mechanisms described encompass altered production of mitochondrial ROS, altered regulation of the nuclear epigenome, affected initiation of apoptosis, and a limiting effect on the production of ribonucleotides and deoxyribonucleotides. 1. Introduction Mitochondria are semiautonomous organelles present in almost all eukaryotic cells in quantities ranging from a single copy to several thousands per cell. Important mitochondrial functions include ATP production by oxidative phosphorylation, β-oxidation of fatty acids, and metabolism of amino acids and lipids. Furthermore, mitochondria have a prominent role in apoptosis initiation. The circular mitochondrial DNA (mtDNA) is more susceptible to DNA damages in comparison to nuclear DNA (nDNA). Importantly, mtDNA molecules are not protected by histones, they are supported with only rudimentary DNA repair and are localized in close proximity to the electron transport chain (ETC), which continuously generates oxidizing products known as reactive oxygen species (ROS). Thus, the mutation rate of mtDNA has been reported to be up to 15-fold higher than observed for nDNA in response to DNA damaging agents [1]. Mitochondrial dysfunction and especially dysfunctions caused by mutations of the mtDNA have been implicated with a wide range of age-related pathologies, including cancers, neurodegenerative diseases and, in general, processes that regulate cellular and organismal aging. The mitochondrial genome encodes peptides essential for the function of the ETC and production of ATP by oxidative phosphorylation. Electrons are primarily donated to the ETC from the Krebs cycle, but other sources also contribute. The human enzyme dihydroorotate dehydrogenase (DHODHase), an integral part of the de novo synthesis of pyrimidines, is coupled to the ETC [2, 3]. The activity of the enzyme is dependent on its ability to transfer electrons to the ETC. ATP is the primary product of oxidative phosphorylation, but certain molecules of ROS are also generated continuously [4, 5]. At subtoxic concentrations, ROS has been demonstrated to function as second messenger molecules proposed to report oxygen availability for oxidative phosphorylation and
Deceleration of Fusion–Fission Cycles Improves Mitochondrial Quality Control during Aging  [PDF]
Marc Thilo Figge ,Andreas S. Reichert ,Michael Meyer-Hermann ,Heinz D. Osiewacz
PLOS Computational Biology , 2012, DOI: 10.1371/journal.pcbi.1002576
Abstract: Mitochondrial dynamics and mitophagy play a key role in ensuring mitochondrial quality control. Impairment thereof was proposed to be causative to neurodegenerative diseases, diabetes, and cancer. Accumulation of mitochondrial dysfunction was further linked to aging. Here we applied a probabilistic modeling approach integrating our current knowledge on mitochondrial biology allowing us to simulate mitochondrial function and quality control during aging in silico. We demonstrate that cycles of fusion and fission and mitophagy indeed are essential for ensuring a high average quality of mitochondria, even under conditions in which random molecular damage is present. Prompted by earlier observations that mitochondrial fission itself can cause a partial drop in mitochondrial membrane potential, we tested the consequences of mitochondrial dynamics being harmful on its own. Next to directly impairing mitochondrial function, pre-existing molecular damage may be propagated and enhanced across the mitochondrial population by content mixing. In this situation, such an infection-like phenomenon impairs mitochondrial quality control progressively. However, when imposing an age-dependent deceleration of cycles of fusion and fission, we observe a delay in the loss of average quality of mitochondria. This provides a rational why fusion and fission rates are reduced during aging and why loss of a mitochondrial fission factor can extend life span in fungi. We propose the ‘mitochondrial infectious damage adaptation’ (MIDA) model according to which a deceleration of fusion–fission cycles reflects a systemic adaptation increasing life span.
Mitochondria and PGC-1α in Aging and Age-Associated Diseases  [PDF]
Tina Wenz
Journal of Aging Research , 2011, DOI: 10.4061/2011/810619
Abstract: Aging is the most significant risk factor for a range of degenerative disease such as cardiovascular, neurodegenerative and metabolic disorders. While the cause of aging and its associated diseases is multifactorial, mitochondrial dysfunction has been implicated in the aging process and the onset and progression of age-associated disorders. Recent studies indicate that maintenance of mitochondrial function is beneficial in the prevention or delay of age-associated diseases. A central molecule seems to be the peroxisome proliferator-activated receptor γ coactivator α (PGC-1α), which is the key regulator of mitochondrial biogenesis. Besides regulating mitochondrial function, PGC-1α targets several other cellular processes and thereby influences cell fate on multiple levels. This paper discusses how mitochondrial function and PGC-1α are affected in age-associated diseases and how modulation of PGC-1α might offer a therapeutic potential for age-related pathology. 1. Introduction In the last 20 years, mitochondrial dysfunction has been recognized as an important contributor to an array of human pathologies [1–3]. Mitochondrial dysfunction is particularly associated with the onset and progression of many age-related disorders such as neurodegenerative and cardiovascular diseases as well as metabolic disorders and age-related muscle wasting. In most cases it is not clear if the mitochondrial dysfunction is causative of the disease or if it is a secondary effect of the disease. Also, it is not understood if mitochondrial dysfunction is an aggravating factor in disease progression. Recent work suggests that maintenance of mitochondrial function is beneficial in at least some age-related diseases [4]. The peroxisome proliferator-activated receptor (PPAR) γ coactivator α (PGC-1α) integrates regulation of mitochondrial function into the modulation of different, tissue-specific metabolic pathways and thereby links mitochondrial function to important cellular signaling pathways that ultimately control cell survival [5, 6]. The following review discusses how mitochondrial dysfunction is associated with age-related diseases and what impact PGC-1α and its targets have in these diseases and their prevention. 2. Mitochondrial Function, ROS, and Aging 2.1. Mitochondrial Function and OXPHOS Mitochondria play a central role in the cell metabolism: besides being key player in apoptosis, mitochondria house major cellular metabolic pathways. The fatty acid oxidation and citric acid cycle convert nutrients absorbed from ingested food to electron donors to NADH and FADH. These
Mitochondrial Inverted Repeats Strongly Correlate with Lifespan: mtDNA Inversions and Aging  [PDF]
Jiang-Nan Yang, Andrei Seluanov, Vera Gorbunova
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0073318
Abstract: Mitochondrial defects are implicated in aging and in a multitude of age-related diseases, such as cancer, heart failure, Parkinson’s disease, and Huntington’s disease. However, it is still unclear how mitochondrial defects arise under normal physiological conditions. Mitochondrial DNA (mtDNA) deletions caused by direct repeats (DRs) are implicated in the formation of mitochondrial defects, however, mitochondrial DRs show relatively weak (Pearson’s r = ?0.22, p<0.002; Spearman’s ρ = ?0.12, p = 0.1) correlation with maximum lifespan (MLS). Here we report a stronger correlation (Pearson’s r = ?0.55, p<10–16; Spearman’s ρ = ?0.52, p<10–14) between mitochondrial inverted repeats (IRs) and lifespan across 202 species of mammals. We show that, in wild type mice under normal conditions, IRs cause inversions, which arise by replication-dependent mechanism. The inversions accumulate with age in the brain and heart. Our data suggest that IR-mediated inversions are more mutagenic than DR-mediated deletions in mtDNA, and impose stronger constraint on lifespan. Our study identifies IR-induced mitochondrial genome instability during mtDNA replication as a potential cause for mitochondrial defects.
Mitochondrial diseases: a review
Daniel Jarovsky,Pedro Shiozawa,Ulisses Augusto Correia Rosalino,Mirna Duarte Barros
Einstein (S?o Paulo) , 2006,
Abstract: Mitochondria are organelles responsible for production of mostenergy through oxidative phosphorylation process (OXPHOS). Itcontains a double strand DNA (mitDNA) of about 16,500 bp encodingtwo ribosomal RNAs and 37 mitochondrial proteins. Mutation inmitDNA may result in multisystem syndromes known asmitochondrial diseases, affecting predominantly tissues thatrequire high levels of ATP such as skeletal muscle (mitochondrialmyopathies), brain (e.g. MELAS, MERRF, LHON e NARP), liver,kidney (Fanconi syndrome), heart and endocrine glands (Pearsonsyndrome). A case of mitochondrial disease was first reported in1962 and correlation of such disease with mutations in mitDNAgained scientific importance in late 1980’s. There are 150 alterationsreported in mitDNA capable of producing metabolic dysfunctionsof clinical relevance. To date, no standard protocol for diagnosis ofmitochondrial diseases has been established, partially due to thewide amplitude of clinical manifestation generally observed. Acombined analysis of clinical data, biochemical, morphologicaland laboratory tests must be performed to evaluate mitochondrialrespiratory chain activity and integrity of nuclear and mitochondrialgenomes. Currently, there are no effective treatments availablefor mitochondrial diseases, but only palliative therapeutics usingconventional strategies to relieve symptoms. Thus, gene therapyemerges as potential therapeutic strategy for more efficienttreatment of mitochondrial diseases.
Mitochondrial and Cell Death Mechanisms in Neurodegenerative Diseases  [PDF]
Lee J. Martin
Pharmaceuticals , 2010, DOI: 10.3390/ph3040839
Abstract: Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS) are the most common human adult-onset neurodegenerative diseases. They are characterized by prominent age-related neurodegeneration in selectively vulnerable neural systems. Some forms of AD, PD, and ALS are inherited, and genes causing these diseases have been identified. Nevertheless, the mechanisms of the neuronal cell death are unresolved. Morphological, biochemical, genetic, as well as cell and animal model studies reveal that mitochondria could have roles in this neurodegeneration. The functions and properties of mitochondria might render subsets of selectively vulnerable neurons intrinsically susceptible to cellular aging and stress and overlying genetic variations, triggering neurodegeneration according to a cell death matrix theory. In AD, alterations in enzymes involved in oxidative phosphorylation, oxidative damage, and mitochondrial binding of Aβ and amyloid precursor protein have been reported. In PD, mutations in putative mitochondrial proteins have been identified and mitochondrial DNA mutations have been found in neurons in the substantia nigra. In ALS, changes occur in mitochondrial respiratory chain enzymes and mitochondrial cell death proteins. Transgenic mouse models of human neurodegenerative disease are beginning to reveal possible principles governing the biology of selective neuronal vulnerability that implicate mitochondria and the mitochondrial permeability transition pore. This review summarizes how mitochondrial pathobiology might contribute to neuronal death in AD, PD, and ALS and could serve as a target for drug therapy.
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