BBA - Bioenergetics (v.1847, #11)
Editorial Board (i).
Is mitochondrial free radical theory of aging getting old? by Elena Rugarli; Aleksandra Trifunovic (1345-1346).
Mitochondrial dysfunction in aging: Much progress but many unresolved questions by Brendan A.I. Payne; Patrick F. Chinnery (1347-1353).
The free radical theory of aging is almost 60 years old. As mitochondria are the principle source of intracellular reactive oxygen species (ROS), this hypothesis suggested a central role for the mitochondrion in normal mammalian aging. In recent years, however, much work has questioned the importance of mitochondrial ROS in driving aging. Conversely new evidence points to other facets of mitochondrial dysfunction which may nevertheless suggest the mitochondrion retains a critical role at the center of a complex web of processes leading to cellular and organismal aging.
Keywords: DNA; Mitochondrial; Aging;
Mitochondrial DNA: Radically free of free-radical driven mutations by Johanna H.K. Kauppila; James B. Stewart (1354-1361).
Mitochondrial DNA has long been posited as a likely target of oxidative damage induced mutation during the ageing process. Research over the past decades has uncovered the accumulation of mitochondrial DNA mutations in association with a mosaic pattern of cells displaying mitochondrial dysfunction in ageing individuals. Unfortunately, the underlying mechanisms are far less straightforward than originally anticipated. Recent research on mitochondria reveals that these genomes are far less helpless than originally envisioned. Additionally, new technologies have allowed us to analyze the mutational signatures of many more somatic mitochondrial DNA mutations, revealing surprising patterns that are inconsistent with a DNA-oxidative damage based hypothesis. In this review, we will discuss these recent observations and new insights into the eccentricities of mitochondrial genetics, and their impact on our understanding of mitochondrial mutations and their role in the ageing process. This article is part of a Special Issue entitled: Mitochondrial Dysfunction in Aging.
Keywords: Mitochondrial DNA; mtDNA; Somatic mutations; Ageing;
Different faces of mitochondrial DNA mutators by Karolina Szczepanowska; Aleksandra Trifunovic (1362-1372).
A number of studies have shown that ageing is associated with increased amounts of mtDNA deletions and/or point mutations in a variety of species as diverse as Caenorhabditis elegans, Drosophila melanogaster, mice, rats, dogs, primates and humans. This detected vulnerability of mtDNA has led to the suggestion that the accumulation of somatic mtDNA mutations might arise from increased oxidative damage and could play an important role in the ageing process by producing cells with a decreased oxidative capacity. However, the vast majority of DNA polymorphisms and disease-causing base-substitution mutations and age-associated mutations that have been detected in human mtDNA are transition mutations. They are likely arising from the slight infidelity of the mitochondrial DNA polymerase. Indeed, transition mutations are also the predominant type of mutation found in mtDNA mutator mice, a model for premature ageing caused by increased mutation load due to the error prone mitochondrial DNA synthesis. These particular misincorporation events could also be exacerbated by dNTP pool imbalances. The role of different repair, replication and maintenance mechanisms that contribute to mtDNA integrity and mutagenesis will be discussed in details in this article. This article is part of a Special Issue entitled: Mitochondrial Dysfunction in Aging.
Keywords: mtDNA mutations; Ageing; mtDNA replication; Mitochondrial DNA repair; POLG;
Mitochondria: Are they causal players in cellular senescence? by Clara Correia-Melo; João F. Passos (1373-1379).
Cellular senescence entails an irreversible cell-cycle arrest characterised by drastic cytomorphological and metabolic changes. In recent years, the implications of cellular senescence in physiological and pathological settings, such as ageing and cancer, have gained firm ground. It is, therefore, important to understand the mechanisms underpinning the establishment and maintenance of senescence. Age-dependent alterations in cellular metabolic processes are greatly driven by changes in mitochondrial function and homeostasis. Classically, mitochondrial dysfunction has been implicated in cellular senescence mainly by promoting oxidative damage-induced cell-cycle arrest; however, emerging data suggests that other mitochondrial-dependent factors play an important role in the induction of senescent phenotypes. Here we review the role of mitochondrial homeostatic mechanisms, mitochondrial metabolites and ROS generation in the signalling pathways leading to the induction and maintenance of cellular senescence and discuss how this may contribute to the ageing process. This article is part of a Special Issue entitled: Mitochondrial Dysfunction in Aging.
Keywords: Mitochondria; Reactive Oxygen Species; Mitochondrial metabolites; Mitochondrial homeostatic mechanisms; Cellular senescence and ageing;
Stem cells, mitochondria and aging by Kati J. Ahlqvist; Anu Suomalainen; Riikka H. Hämäläinen (1380-1386).
Decline in metabolism and regenerative potential of tissues are common characteristics of aging. Regeneration is maintained by somatic stem cells (SSCs), which require tightly controlled energy metabolism and genomic integrity for their homeostasis. Recent data indicate that mitochondrial dysfunction may compromise this homeostasis, and thereby contribute to tissue degeneration and aging. Progeroid Mutator mouse, accumulating random mtDNA point mutations in their SSCs, showed disturbed SSC homeostasis, emphasizing the importance of mtDNA integrity for stem cells. The mechanism involved changes in cellular redox-environment, including subtle increase in reactive oxygen species (H2O2 and superoxide anion), which did not cause oxidative damage, but disrupted SSC function. Mitochondrial metabolism appears therefore to be an important regulator of SSC fate determination, and defects in it in SSCs may underlie premature aging. Here we review the current knowledge of mitochondrial contribution to SSC dysfunction and aging. This article is part of a Special Issue entitled: Mitochondrial Dysfunction in Aging.
Keywords: Mitochondria; Aging; Stem cells; mtDNA; Redox balance;
The role of mitochondrial dysfunction in age-related diseases by Rebecca K. Lane; Tyler Hilsabeck; Shane L. Rea (1387-1400).
The aging process is accompanied by the onset of disease and a general decline in wellness. Insights into the aging process have revealed a number of cellular hallmarks of aging, among these epigenetic alterations, loss of proteostasis, mitochondrial dysfunction, cellular senescence, and stem cell exhaustion. Mitochondrial dysfunction increasingly appears to be a common factor connecting several of these hallmarks, driving the aging process and afflicting tissues throughout the body. Recent research has uncovered a much more complex involvement of mitochondria in the cell than has previously been appreciated and revealed novel ways in which mitochondrial defects feed into disease pathology. In this review we evaluate ways in which problems in mitochondria contribute to disease beyond the well-known mechanisms of oxidative stress and bioenergetic deficits, and we predict the direction that mitochondrial disease research will take in years to come.
Keywords: Mitochondria; Atherosclerosis; Neurodegeneration; Stem cells; Osteoporosis; Sirtuins; Immunity; Aging;
Mitochondrial DNA mutations in neurodegeneration by Michael J. Keogh; Patrick F. Chinnery (1401-1411).
Mitochondrial dysfunction is observed in both the aging brain, and as a core feature of several neurodegenerative diseases. A central mechanism mediating this dysfunction is acquired molecular damage to mitochondrial DNA (mtDNA). In addition, inherited stable mtDNA variation (mitochondrial haplogroups), and inherited low level variants (heteroplasmy) have also been associated with the development of neurodegenerative disease and premature neural aging respectively. Herein we review the evidence for both inherited and acquired mtDNA mutations contributing to neural aging and neurodegenerative disease. This article is part of a Special Issue entitled: Mitochondrial Dysfunction in Aging.
Keywords: DNA; Mitochondrial; Aging; Parkinson disease; Alzheimer disease; Lewy body disease;
Mitochondria, autophagy and age-associated neurodegenerative diseases: New insights into a complex interplay by Eirini Lionaki; Maria Markaki; Konstantinos Palikaras; Nektarios Tavernarakis (1412-1423).
Mitochondria represent the major bioenergetic hub coordinating cellular and organismal homeostasis. The underlying causes of many pathologies tormenting humans converge on impaired mitochondrial maintenance. Mitochondria-specific autophagy (mitophagy), a cellular catabolic process targeting mitochondria, holds a prominent role in mitochondrial quality control. In addition to core autophagic machinery components, mitophagy exploits a variety of molecules that identify damaged or superfluous mitochondria and mediate their elimination. Signaling pathways integrating environmental and genetic stimuli interact with key mitophagy effectors to activate cellular stress response mechanisms, ultimately modulating health and lifespan. Here, we review the signaling cascades and molecular mechanisms that govern the process of mitophagy and discuss their involvement in ageing and neurodegeneration. This article is part of a Special Issue entitled: Mitochondrial Dysfunction in Aging.
Keywords: Energy homeostasis; Mitophagy; PINK1; Parkin; Neurodegenerative diseases; Stress response;
Mitochondrial dysfunction in cardiac aging by Autumn Tocchi; Ellen K. Quarles; Nathan Basisty; Lemuel Gitari; Peter S. Rabinovitch (1424-1433).
Cardiovascular diseases are the leading cause of death in most developed nations. While it has received the least public attention, aging is the dominant risk factor for developing cardiovascular diseases, as the prevalence of cardiovascular diseases increases dramatically with increasing age. Cardiac aging is an intrinsic process that results in impaired cardiac function, along with cellular and molecular changes. Mitochondria play a great role in these processes, as cardiac function is an energetically demanding process. In this review, we examine mitochondrial dysfunction in cardiac aging. Recent research has demonstrated that mitochondrial dysfunction can disrupt morphology, signaling pathways, and protein interactions; conversely, mitochondrial homeostasis is maintained by mechanisms that include fission/fusion, autophagy, and unfolded protein responses. Finally, we describe some of the recent findings in mitochondrial targeted treatments to help meet the challenges of mitochondrial dysfunction in aging.
Keywords: Mitochondrial dysfunction; Heart; Aging; Mitostasis;
Dietary restriction, mitochondrial function and aging: from yeast to humans by Andrea Ruetenik; Antoni Barrientos (1434-1447).
Dietary restriction (DR) attenuates many detrimental effects of aging and consequently promotes health and increases longevity across organisms. While over the last 15 years extensive research has been devoted towards understanding the biology of aging, the precise mechanistic aspects of DR are yet to be settled. Abundant experimental evidence indicates that the DR effect on stimulating health impinges several metabolic and stress-resistance pathways. Downstream effects of these pathways include a reduction in cellular damage induced by oxidative stress, enhanced efficiency of mitochondrial functions and maintenance of mitochondrial dynamics and quality control, thereby attenuating age-related declines in mitochondrial function. However, the literature also accumulates conflicting evidence regarding how DR ameliorates mitochondrial performance and whether that is enough to slow age-dependent cellular and organismal deterioration. Here, we will summarize the current knowledge about how and to which extent the influence of different DR regimes on mitochondrial biogenesis and function contribute to postpone the detrimental effects of aging on healthspan and lifespan. This article is part of a Special Issue entitled: Mitochondrial Dysfunction in Aging.
Keywords: Dietary restriction; Mitochondria; OXPHOS; TORC1; Aging; Longevity;
UPRmt-mediated cytoprotection and organismal aging by Anna M. Schulz; Cole M. Haynes (1448-1456).
Time- or age-dependent accumulation of mitochondrial damage and dysfunction is strongly associated with aging . Thus, a major biomedical goal is to identify and therapeutically manipulate those inherent programs that protect against mitochondrial dysfunction to promote cell survival and organismal health. The mitochondrial unfolded protein response (UPRmt) is such a protective transcriptional response mediated by mitochondrial-to-nuclear signaling that includes mitochondrial proteostasis genes to stabilize mitochondrial function, metabolic adaptations, as well as an innate immunity program. Here, we review the UPRmt and its role during a variety of forms of mitochondrial dysfunction including those caused by mutations in respiratory chain genes as well as upon exposure to pathogens that produce mitochondrial toxins. We also review recent data in support of and against the emerging role of the UPRmt during aging and longevity. This article is part of a Special Issue entitled: Mitochondrial Dysfunction in Aging.
Keywords: Mitochondrial dysfunction; ATFS-1; Mitochondrial unfolded protein response; Metabolism; Innate immunity;
Analysis of the effect of the mitochondrial prohibitin complex, a context-dependent modulator of longevity, on the C. elegans metabolome by Artur B. Lourenço; Celia Muñoz-Jiménez; Mónica Venegas-Calerón; Marta Artal-Sanz (1457-1468).
The mitochondrial prohibitin complex, composed of two proteins, PHB-1 and PHB-2, is a context-dependent modulator of longevity. Specifically, prohibitin deficiency shortens the lifespan of otherwise wild type worms, while it dramatically extends the lifespan under compromised metabolic conditions. This extremely intriguingly phenotype has been linked to alterations in mitochondrial function and in fat metabolism. However, the true function of the mitochondrial prohibitin complex remains elusive. Here, we used gas chromatography coupled to a flame ionization detector (GC/FID) and 1H NMR spectroscopy to gain molecular insights into the effect of prohibitin depletion on the Caenorhabditis elegans metabolome. We analysed the effect of prohibitin deficiency in two different developmental stages and under two different conditions, which result in opposing longevity phenotypes, namely wild type worms and daf-2(e1370) insulin signalling deficient mutants. Prohibitin depletion was shown to alter the fatty acid (GC/FID) and 1H NMR metabolic profiles of wild type animals both at the fourth larval stage of development (L4) and at the young adult (YA) stage, while being more pronounced at the later stage. Furthermore, wild type and the diapause mutant daf-2(e1370), either expressing or not prohibitin, were clearly distinguishable based on their metabolic profiles, revealing changes in fatty acid composition, as well as in carbohydrate and amino acid metabolism. Moreover, the metabolic data indicate that daf-2(e1370) mutants are more robust than the wild type animals to changes induced by prohibitin depletion. The impact of prohibitin depletion on the C. elegans metabolome will be discussed herein in the scope of its effect on longevity. This article is part of a Special Issue entitled: Mitochondrial Dysfunction in Aging. Guest Editor: Aleksandra Trifunovic
Keywords: Prohibitin; Insulin signalling; Mitochondria; C. elegans; Longevity; Metabolomics;
An automated phenotype-based microscopy screen to identify pro-longevity interventions acting through mitochondria in C. elegans by Silvia Maglioni; Nayna Arsalan; Luigi Franchi; Alexander Hurd; Anthony W. Opipari; Gary D. Glick; Natascia Ventura (1469-1478).
Mitochondria are multifunctional organelles that play a central role in cellular homeostasis. Severe mitochondrial dysfunction leads to life-threatening diseases in humans and accelerates the aging process. Surprisingly, moderate reduction of mitochondrial function in different species has anti-aging effects. High-throughput screenings in the nematode Caenorhabditis elegans lead to the identification of several pro-longevity genetic and pharmacological interventions. Large-scale screens, however, are manual, subjective, time consuming and costly. These limitations could be reduced by the identification of automatically quantifiable biomarkers of healthy aging. In this study we exploit the distinct and reproducible phenotypes described in C. elegans upon different levels of mitochondrial alteration to develop an automated high-content strategy to identify new potential pro-longevity interventions. Utilizing the microscopy platform Cellomics ArrayScan Reader, we optimize a workflow to automatically and reliably quantify the discrete phenotypic readouts associated with different degrees of silencing of mitochondrial respiratory chain regulatory proteins, and validate the approach with mitochondrial-targeting drugs known to extend lifespan in C. elegans. Finally, we report that a new mitochondrial ATPase modulator matches our screening phenotypic criteria and extends nematode's lifespan thus providing the proof of principle that our strategy could be exploited to identify novel mitochondrial-targeted drugs with pro-longevity activity. This article is part of a Special Issue entitled: Mitochondrial Dysfunction in Aging.Display Omitted
Keywords: Aging; C. elegans; High-content screening; Mitochondria; Mit mutant's phenotypes; Phenotypic biomarkers;