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Mitochondria and Aging
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Mitochondria and Aging

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (31 October 2017) | Viewed by 98713

Special Issue Editors

Prof. Dr. Konstantin Khrapko

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Guest Editor
Department of Biology, Northeastern University, Boston, MA 02115, USA
Interests: basic biology of aging; dynamics of intracellular mitochondrial population; nuclear pseudogenes of mtDNA - NUMTs; human evolution; somatic mitochondrial DNA mutations, their abundance and relevance to human aging and disease
Special Issues, Collections and Topics in MDPI journals
Dr. Dori Woods

E-Mail Website
Guest Editor
Department of Biology, Northeastern University, Boston, MA, USA
Interests: female germline stem cells; mitochondria in health and disease; aging; reproductive health
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Aging is a remarkably complex phenomenon. Some of us believe that this complexity is no coincidence, that evolution of longevity inevitably drives the aging process to be complex and redundant. We only start to appreciate this complexity.

The Mitochondrial Theory of Aging gives an example of this trend. The Theory has emerged from Dedham Harman’s idea that mitochondrial reactive oxygen species are the primary driver of aging. Today we appreciate that, first, ROS are not necessarily bad and may actually have ameliorating effect on the aging organism, e.g., during exercise. Second, detrimental processes in the mitochondria are not necessarily related to ROS production, e.g., clonally accumulating somatic mtDNA mutations that merely impede mitochondrial respiration. In fact, at present there are several independent theories relating processes in mitochondria to aging. The apparent complexity of aging implies that these theories need not be competitors, contending for the title of “the Correct Theory of Aging”. I fact many of them may be equally correct and reflect the different facets of the aging process.

In this Special Issue, we welcome reviews, new methods, and original articles covering many possible roles the mitochondria may play in the aging process. We look forward to your contributions.

Prof. Dr. Konstantin Khrapko
Prof. Dr. Dori Woods
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • mutation
  • mtDNA
  • mitochondria
  • exercise
  • aging
  • mitochondrial dysfunction
  • mitochondrial theory of aging
  • energetics and aging
  • oxidative damage
  • oxidative stress
  • protein turnover
  • mitochondrial dynamics
  • aging of the germ line
  • lipid peroxidation
  • apoptosis
  • evolution of aging
  • neurodegeneration
  • Alzheimer disease
  • Parkinson disease
  • sarcopenia

Published Papers (11 papers)

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Research

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21 pages, 4846 KiB  
Article
Mitochondrial HTRA2 Plays a Positive, Protective Role in Dictyostelium discoideum but Is Cytotoxic When Overexpressed
by Suwei Chen, Oana Sanislav, Sarah J. Annesley and Paul R. Fisher
Genes 2018, 9(7), 355; https://doi.org/10.3390/genes9070355 - 16 Jul 2018
Cited by 9 | Viewed by 3444
Abstract
HTRA2 is a mitochondrial protein, mutations in which are associated with autosomal dominant late-onset Parkinson’s disease (PD). The mechanisms by which HTRA2 mutations result in PD are poorly understood. HTRA2 is proposed to play a proteolytic role in protein quality control and homeostasis [...] Read more.
HTRA2 is a mitochondrial protein, mutations in which are associated with autosomal dominant late-onset Parkinson’s disease (PD). The mechanisms by which HTRA2 mutations result in PD are poorly understood. HTRA2 is proposed to play a proteolytic role in protein quality control and homeostasis in the mitochondrial intermembrane space. Its loss has been reported to result in accumulation of unfolded and misfolded proteins. However, in at least one case, PD-associated HTRA2 mutation can cause its hyperphosphorylation, possibly resulting in protease hyperactivity. The consequences of overactive mitochondrial HTRA2 are not clear. Dictyostelium discoideum provides a well-established model for studying mitochondrial dysfunction, such as has been implicated in the pathology of PD. We identified a single homologue of human HTRA2 encoded in the Dictyostelium discoideum genome and showed that it is localized to the mitochondria where it plays a cytoprotective role. Knockdown of HTRA2 expression caused defective morphogenesis in the multicellular phases of the Dictyostelium life cycle. In vegetative cells, it did not impair mitochondrial respiration but nonetheless caused slow growth (particularly when the cells were utilizing a bacterial food source), unaccompanied by significant defects in the requisite endocytic pathways. Despite its protective roles, we could not ectopically overexpress wild type HTRA2, suggesting that mitochondrial HTRA2 hyperactivity is lethal. This toxicity was abolished by replacing the essential catalytic serine S300 with alanine to ablate serine protease activity. Overexpression of protease-dead HTRA2 phenocopied the effects of knockdown, suggesting that the mutant protein competitively inhibits interactions between wild type HTRA2 and its binding partners. Our results show that cytopathological dysfunction can be caused either by too little or too much HTRA2 activity in the mitochondria and suggest that either could be a cause of PD. Full article
(This article belongs to the Special Issue Mitochondria and Aging)
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5712 KiB  
Article
Proliferation Cycle Causes Age Dependent Mitochondrial Deficiencies and Contributes to the Aging of Stem Cells
by Qiuting Ren, Fan Zhang and Hong Xu
Genes 2017, 8(12), 397; https://doi.org/10.3390/genes8120397 - 19 Dec 2017
Cited by 4 | Viewed by 4720
Abstract
In addition to chronological aging, stem cells are also subject to proliferative aging during the adult life span. However, the consequences of proliferative cycle and their contributions to stem cells aging have not been well investigated. Using Drosophila female germ line stem cells [...] Read more.
In addition to chronological aging, stem cells are also subject to proliferative aging during the adult life span. However, the consequences of proliferative cycle and their contributions to stem cells aging have not been well investigated. Using Drosophila female germ line stem cells as a model, we found that the replication cycle leads to the age dependent decline of female fecundity, and is a major factor causing developmental abnormalities in the progeny of old females. The proliferative aging does not cause telomere shortening, but causes an accumulation of mitochondrial DNA (mtDNA) mutations or rearrangements at the control region. We propose that damaging mutations on mtDNA caused by accumulation of proliferation cycles in aged stem cells may disrupt mitochondrial respiration chain and impair mtDNA replication and represent a conserved mechanism underlying stem cell aging. Full article
(This article belongs to the Special Issue Mitochondria and Aging)
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Review

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19 pages, 2457 KiB  
Review
Influence of Maternal Aging on Mitochondrial Heterogeneity, Inheritance, and Function in Oocytes and Preimplantation Embryos
by Dori C. Woods, Konstantin Khrapko and Jonathan L. Tilly
Genes 2018, 9(5), 265; https://doi.org/10.3390/genes9050265 - 21 May 2018
Cited by 34 | Viewed by 6565
Abstract
Contrasting the equal contribution of nuclear genetic material from maternal and paternal sources to offspring, passage of mitochondria, and thus mitochondrial DNA (mtDNA), is uniparental through the egg. Since mitochondria in eggs are ancestral to all somatic mitochondria of the next generation and [...] Read more.
Contrasting the equal contribution of nuclear genetic material from maternal and paternal sources to offspring, passage of mitochondria, and thus mitochondrial DNA (mtDNA), is uniparental through the egg. Since mitochondria in eggs are ancestral to all somatic mitochondria of the next generation and to all cells of future generations, oocytes must prepare for the high energetic demands of maturation, fertilization and embryogenesis while simultaneously ensuring that their mitochondrial genomes are inherited in an undamaged state. Although significant effort has been made to understand how the mtDNA bottleneck and purifying selection act coordinately to prevent silent and unchecked spreading of invisible mtDNA mutations through the female germ line across successive generations, it is unknown if and how somatic cells of the immediate next generation are spared from inheritance of detrimental mtDNA molecules. Here, we review unique aspects of mitochondrial activity and segregation in eggs and early embryos, and how these events play into embryonic developmental competency in the face of advancing maternal age. Full article
(This article belongs to the Special Issue Mitochondria and Aging)
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9 pages, 223 KiB  
Review
Brain Mitochondria, Aging, and Parkinson’s Disease
by Mario Rango and Nereo Bresolin
Genes 2018, 9(5), 250; https://doi.org/10.3390/genes9050250 - 11 May 2018
Cited by 49 | Viewed by 5948
Abstract
This paper reconsiders the role of mitochondria in aging and in Parkinson’s Disease (PD). The most important risk factor for PD is aging. Alterations in mitochondrial activity are typical of aging. Mitochondrial aging is characterized by decreased oxidative phosphorylation, proteasome activity decrease, altered [...] Read more.
This paper reconsiders the role of mitochondria in aging and in Parkinson’s Disease (PD). The most important risk factor for PD is aging. Alterations in mitochondrial activity are typical of aging. Mitochondrial aging is characterized by decreased oxidative phosphorylation, proteasome activity decrease, altered autophagy, and mitochondrial dysfunction. Beyond declined oxidative phosphorylation, mitochondrial dysfunction consists of a decline of beta-oxidation as well as of the Krebs cycle. Not inherited mitochondrial DNA (mtDNA) mutations are acquired over time and parallel the decrease in oxidative phosphorylation. Many of these mitochondrial alterations are also found in the PD brain specifically in the substantia nigra (SN). mtDNA deletions and development of respiratory chain deficiency in SN neurons of aged individuals as well as of individuals with PD converge towards a shared pathway, which leads to neuronal dysfunction and death. Finally, several nuclear genes that are mutated in hereditary PD are usually implicated in mitochondrial functioning to a various extent and their mutation may cause mitochondrial impairment. In conclusion, a tight link exists between mitochondria, aging, and PD. Full article
(This article belongs to the Special Issue Mitochondria and Aging)
12 pages, 5971 KiB  
Review
Roles of Mitochondrial DNA Mutations in Stem Cell Ageing
by Tianhong Su, Doug M. Turnbull and Laura C. Greaves
Genes 2018, 9(4), 182; https://doi.org/10.3390/genes9040182 - 27 Mar 2018
Cited by 16 | Viewed by 8480
Abstract
Mitochondrial DNA (mtDNA) mutations accumulate in somatic stem cells during ageing and cause mitochondrial dysfunction. In this review, we summarize the studies that link mtDNA mutations to stem cell ageing. We discuss the age-related behaviours of the somatic mtDNA mutations in stem cell [...] Read more.
Mitochondrial DNA (mtDNA) mutations accumulate in somatic stem cells during ageing and cause mitochondrial dysfunction. In this review, we summarize the studies that link mtDNA mutations to stem cell ageing. We discuss the age-related behaviours of the somatic mtDNA mutations in stem cell populations and how they potentially contribute to stem cell ageing by altering mitochondrial properties in humans and in mtDNA-mutator mice. We also draw attention to the diverse fates of the mtDNA mutations with different origins during ageing, with potential selective pressures on the germline inherited but not the somatic mtDNA mutations. Full article
(This article belongs to the Special Issue Mitochondria and Aging)
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13 pages, 1531 KiB  
Review
Is There Still Any Role for Oxidative Stress in Mitochondrial DNA-Dependent Aging?
by Gábor Zsurka, Viktoriya Peeva, Alexander Kotlyar and Wolfram S. Kunz
Genes 2018, 9(4), 175; https://doi.org/10.3390/genes9040175 - 21 Mar 2018
Cited by 41 | Viewed by 5781
Abstract
Recent deep sequencing data has provided compelling evidence that the spectrum of somatic point mutations in mitochondrial DNA (mtDNA) in aging tissues lacks G > T transversion mutations. This fact cannot, however, be used as an argument for the missing contribution of reactive [...] Read more.
Recent deep sequencing data has provided compelling evidence that the spectrum of somatic point mutations in mitochondrial DNA (mtDNA) in aging tissues lacks G > T transversion mutations. This fact cannot, however, be used as an argument for the missing contribution of reactive oxygen species (ROS) to mitochondria-related aging because it is probably caused by the nucleotide selectivity of mitochondrial DNA polymerase γ (POLG). In contrast to point mutations, the age-dependent accumulation of mitochondrial DNA deletions is, in light of recent experimental data, still explainable by the segregation of mutant molecules generated by the direct mutagenic effects of ROS (in particular, of HO· radicals formed from H2O2 by a Fenton reaction). The source of ROS remains controversial, because the mitochondrial contribution to tissue ROS production is probably lower than previously thought. Importantly, in the discussion about the potential role of oxidative stress in mitochondria-dependent aging, ROS generated by inflammation-linked processes and the distribution of free iron also require careful consideration. Full article
(This article belongs to the Special Issue Mitochondria and Aging)
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20 pages, 615 KiB  
Review
Targeting Mitochondria to Counteract Age-Related Cellular Dysfunction
by Corina T. Madreiter-Sokolowski, Armin A. Sokolowski, Markus Waldeck-Weiermair, Roland Malli and Wolfgang F. Graier
Genes 2018, 9(3), 165; https://doi.org/10.3390/genes9030165 - 16 Mar 2018
Cited by 38 | Viewed by 9464
Abstract
Senescence is related to the loss of cellular homeostasis and functions, which leads to a progressive decline in physiological ability and to aging-associated diseases. Since mitochondria are essential to energy supply, cell differentiation, cell cycle control, intracellular signaling and Ca2+ sequestration, fine-tuning [...] Read more.
Senescence is related to the loss of cellular homeostasis and functions, which leads to a progressive decline in physiological ability and to aging-associated diseases. Since mitochondria are essential to energy supply, cell differentiation, cell cycle control, intracellular signaling and Ca2+ sequestration, fine-tuning mitochondrial activity appropriately, is a tightrope walk during aging. For instance, the mitochondrial oxidative phosphorylation (OXPHOS) ensures a supply of adenosine triphosphate (ATP), but is also the main source of potentially harmful levels of reactive oxygen species (ROS). Moreover, mitochondrial function is strongly linked to mitochondrial Ca2+ homeostasis and mitochondrial shape, which undergo various alterations during aging. Since mitochondria play such a critical role in an organism’s process of aging, they also offer promising targets for manipulation of senescent cellular functions. Accordingly, interventions delaying the onset of age-associated disorders involve the manipulation of mitochondrial function, including caloric restriction (CR) or exercise, as well as drugs, such as metformin, aspirin, and polyphenols. In this review, we discuss mitochondria’s role in and impact on cellular aging and their potential to serve as a target for therapeutic interventions against age-related cellular dysfunction. Full article
(This article belongs to the Special Issue Mitochondria and Aging)
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13 pages, 444 KiB  
Review
The Aging Mitochondria
by Pierre Theurey and Paola Pizzo
Genes 2018, 9(1), 22; https://doi.org/10.3390/genes9010022 - 09 Jan 2018
Cited by 69 | Viewed by 20304
Abstract
Mitochondrial dysfunction is a central event in many pathologies and contributes as well to age-related processes. However, distinguishing between primary mitochondrial dysfunction driving aging and a secondary mitochondrial impairment resulting from other cell alterations remains challenging. Indeed, even though mitochondria undeniably play a [...] Read more.
Mitochondrial dysfunction is a central event in many pathologies and contributes as well to age-related processes. However, distinguishing between primary mitochondrial dysfunction driving aging and a secondary mitochondrial impairment resulting from other cell alterations remains challenging. Indeed, even though mitochondria undeniably play a crucial role in aging pathways at the cellular and organismal level, the original hypothesis in which mitochondrial dysfunction and production of free radicals represent the main driving force of cell degeneration has been strongly challenged. In this review, we will first describe mitochondrial dysfunctions observed in aged tissue, and how these features have been linked to mitochondrial reactive oxygen species (ROS)–mediated cell damage and mitochondrial DNA (mtDNA) mutations. We will also discuss the clues that led to consider mitochondria as the starting point in the aging process, and how recent research has showed that the mitochondria aging axis represents instead a more complex and multifactorial signaling pathway. New working hypothesis will be also presented in which mitochondria are considered at the center of a complex web of cell dysfunctions that eventually leads to cell senescence and death. Full article
(This article belongs to the Special Issue Mitochondria and Aging)
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1141 KiB  
Review
The Mitochondrial Basis of Aging and Age-Related Disorders
by Sarika Srivastava
Genes 2017, 8(12), 398; https://doi.org/10.3390/genes8120398 - 19 Dec 2017
Cited by 210 | Viewed by 21240
Abstract
Aging is a natural phenomenon characterized by progressive decline in tissue and organ function leading to increased risk of disease and mortality. Among diverse factors that contribute to human aging, the mitochondrial dysfunction has emerged as one of the key hallmarks of aging [...] Read more.
Aging is a natural phenomenon characterized by progressive decline in tissue and organ function leading to increased risk of disease and mortality. Among diverse factors that contribute to human aging, the mitochondrial dysfunction has emerged as one of the key hallmarks of aging process and is linked to the development of numerous age-related pathologies including metabolic syndrome, neurodegenerative disorders, cardiovascular diseases and cancer. Mitochondria are central in the regulation of energy and metabolic homeostasis, and harbor a complex quality control system that limits mitochondrial damage to ensure mitochondrial integrity and function. The intricate regulatory network that balances the generation of new and removal of damaged mitochondria forms the basis of aging and longevity. Here, I will review our current understanding on how mitochondrial functional decline contributes to aging, including the role of somatic mitochondrial DNA (mtDNA) mutations, reactive oxygen species (ROS), mitochondrial dynamics and quality control pathways. I will further discuss the emerging evidence on how dysregulated mitochondrial dynamics, mitochondrial biogenesis and turnover mechanisms contribute to the pathogenesis of age-related disorders. Strategies aimed to enhance mitochondrial function by targeting mitochondrial dynamics, quality control, and mitohormesis pathways might promote healthy aging, protect against age-related diseases, and mediate longevity. Full article
(This article belongs to the Special Issue Mitochondria and Aging)
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530 KiB  
Review
Mitochondria and α-Synuclein: Friends or Foes in the Pathogenesis of Parkinson’s Disease?
by Gaia Faustini, Federica Bono, Alessandra Valerio, Marina Pizzi, PierFranco Spano and Arianna Bellucci
Genes 2017, 8(12), 377; https://doi.org/10.3390/genes8120377 - 08 Dec 2017
Cited by 45 | Viewed by 6974
Abstract
Parkinson’s disease (PD) is a movement disorder characterized by dopaminergic nigrostriatal neuron degeneration and the formation of Lewy bodies (LB), pathological inclusions containing fibrils that are mainly composed of α-synuclein. Dopaminergic neurons, for their intrinsic characteristics, have a high energy demand that relies [...] Read more.
Parkinson’s disease (PD) is a movement disorder characterized by dopaminergic nigrostriatal neuron degeneration and the formation of Lewy bodies (LB), pathological inclusions containing fibrils that are mainly composed of α-synuclein. Dopaminergic neurons, for their intrinsic characteristics, have a high energy demand that relies on the efficiency of the mitochondria respiratory chain. Dysregulations of mitochondria, deriving from alterations of complex I protein or oxidative DNA damage, change the trafficking, size and morphology of these organelles. Of note, these mitochondrial bioenergetics defects have been related to PD. A series of experimental evidence supports that α-synuclein physiological action is relevant for mitochondrial homeostasis, while its pathological aggregation can negatively impinge on mitochondrial function. It thus appears that imbalances in the equilibrium between the reciprocal modulatory action of mitochondria and α-synuclein can contribute to PD onset by inducing neuronal impairment. This review will try to highlight the role of physiological and pathological α-synuclein in the modulation of mitochondrial functions. Full article
(This article belongs to the Special Issue Mitochondria and Aging)
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Other

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12 pages, 1243 KiB  
Perspective
Resolving the Enigma of the Clonal Expansion of mtDNA Deletions
by Axel Kowald and Thomas B.L. Kirkwood
Genes 2018, 9(3), 126; https://doi.org/10.3390/genes9030126 - 27 Feb 2018
Cited by 22 | Viewed by 4917
Abstract
Mitochondria are cell organelles that are special since they contain their own genetic material in the form of mitochondrial DNA (mtDNA). Damage and mutations of mtDNA are not only involved in several inherited human diseases but are also widely thought to play an [...] Read more.
Mitochondria are cell organelles that are special since they contain their own genetic material in the form of mitochondrial DNA (mtDNA). Damage and mutations of mtDNA are not only involved in several inherited human diseases but are also widely thought to play an important role during aging. In both cases, point mutations or large deletions accumulate inside cells, leading to functional impairment once a certain threshold has been surpassed. In most cases, it is a single type of mutant that clonally expands and out-competes the wild type mtDNA, with different mutant molecules being amplified in different cells. The challenge is to explain where the selection advantage for the accumulation comes from, why such a large range of different deletions seem to possess this advantage, and how this process can scale to species with different lifespans such as those of rats and man. From this perspective, we provide an overview of current ideas, present an update of our own proposal, and discuss the wider relevance of the phenomenon for aging. Full article
(This article belongs to the Special Issue Mitochondria and Aging)
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