Complex Transmission Patterns and Age-Related Dynamics of a Selfish mtDNA Deletion

Abstract Despite wide-ranging implications of selfish mitochondrial DNA (mtDNA) elements for human disease and topics in evolutionary biology (e.g., speciation), the forces controlling their formation, age-related accumulation, and offspring transmission remain largely unknown. Selfish mtDNA poses a significant challenge to genome integrity, mitochondrial function, and organismal fitness. For instance, numerous human diseases are associated with mtDNA mutations; however, few genetic systems can simultaneously represent pathogenic mitochondrial genome evolution and inheritance. The nematode Caenorhabditis briggsae is one such system. Natural C. briggsae isolates harbor varying levels of a large-scale deletion affecting the mitochondrial nduo-5 gene, termed nad5Δ. A subset of these isolates contains putative compensatory mutations that may reduce the risk of deletion formation. We studied the dynamics of nad5Δ heteroplasmy levels during animal development and transmission from mothers to offspring in genetically diverse C. briggsae natural isolates. Results support previous work demonstrating that nad5Δ is a selfish element and that heteroplasmy levels of this deletion can be quite plastic, exhibiting high degrees of inter-family variability and divergence between generations. The latter is consistent with a mitochondrial bottleneck effect, and contrasts with previous findings from a laboratory-derived model uaDf5 mtDNA deletion in C. elegans. However, we also found evidence for among-isolate differences in the ability to limit nad5Δ accumulation, the pattern of which suggested that forces other than the compensatory mutations are important in protecting individuals and populations from rampant mtDNA deletion expansion over short time scales.

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Oxidative Stress, Mitochondrial DNA Mutation, and Impairment of Antioxidant Enzymes in Aging

Experimental Biology and Medicine ◽

10.1177/153537020222700901 ◽

2002 ◽

Vol 227 (9) ◽

pp. 671-682 ◽

Cited By ~ 377

Author(s):

Yau-Huei Wei ◽

Hsin-Chen Lee

Keyword(s):

Oxidative Stress ◽

Mitochondrial Dna ◽

Antioxidant Enzymes ◽

Oxidative Damage ◽

Large Scale ◽

Wide Spectrum ◽

Radical Scavenging ◽

Mtdna Mutations ◽

Enhanced Production ◽

Age Related

Mitochondria do not only produce less ATP, but they also increase the production of reactive oxygen species (ROS) as byproducts of aerobic metabolism in the aging tissues of the human and animals. It is now generally accepted that aging-associated respiratory function decline can result in enhanced production of ROS in mitochondria. Moreover, the activities of free radical-scavenging enzymes are altered in the aging process. The concurrent age-related changes of these two systems result in the elevation of oxidative stress in aging tissues. Within a certain concentration range, ROS may induce stress response of the cells by altering expression of respiratory genes to uphold the energy metabolism to rescue the cell. However, beyond the threshold, ROS may cause a wide spectrum of oxidative damage to various cellular components to result in cell death or elicit apoptosis by induction of mitochondrial membrane permeability transition and release of apoptogenic factors such as cytochrome c. Moreover, oxidative damage and large-scale deletion and duplication of mitochondrial DNA (mtDNA) have been found to increase with age in various tissues of the human. Mitochondria act like a biosensor of oxidative stress and they enable cell to undergo changes in aging and age-related diseases. On the other hand, it has recently been demonstrated that impairment in mitochondrial respiration and oxidative phosphorylation elicits an increase in oxidative stress and causes a host of mtDNA rearrangements and deletions. Here, we review work done in the past few years to support our view that oxidative stress and oxidative damage are a result of concurrent accumulation of mtDNA mutations and defective antioxidant enzymes in human aging.

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NemaLife: A structured microfluidic culture device optimized for aging studies in crawling C. elegans

10.1101/675827 ◽

2019 ◽

Cited By ~ 4

Author(s):

Mizanur Rahman ◽

Hunter Edwards ◽

Nikolajs Birze ◽

Rebecca Gabrilska ◽

Kendra P. Rumbaugh ◽

...

Keyword(s):

Large Scale ◽

The Body ◽

Physiological Data ◽

Aging Research ◽

C Elegans ◽

Age Related ◽

Technology Platforms ◽

Aging Studies ◽

Pharyngeal Pumping ◽

Culture Maintenance

AbstractCaenorhabditis elegans is a powerful animal model in aging research. Standard longevity assays on agar plates involve the tedious task of picking and transferring animals to prevent younger progeny from contaminating age-synchronized adult populations. Large-scale studies employ progeny-blocking drugs or sterile mutants to avoid progeny contamination, but such manipulations change adult physiology and alter the influence of reproduction on normal aging. Moreover, for some agar growth-based technology platforms, such as automated lifespan machines, reagents such as food or drugs cannot be readily added/removed after initiation of the study. Current microfluidic approaches are well-suited to address these limitations, but in their liquid-based environments animals swim rather than crawl, introducing swim-induced stress in the lifespan analysis. Here we report a simple microfluidic device that we call NemaLife that features: 1) an optimized micropillar arena in which animals can crawl, 2) sieve channels that separate progeny and prevent the loss of adults from the arena during culture maintenance, and 3) ports which allow rapid accessibility to feed the adult-only population and introduce reagents as needed. Culture maintenance and liquid manipulation are performed with simple hand-held syringes to facilitate integration of our technology into general laboratory protocols. Additionally, device geometry and feeding protocols were designed to emulate the body gait, locomotion, and lifespan of animals reared on agar. We validated our approach with longevity analyses of classical aging mutants (daf-2, age-1, eat-2, and daf-16) and animals subjected to RNAi knockdown of age-related genes (age-1 and daf-16). We also showed that healthspan measures such as pharyngeal pumping and tap-induced stimulated reversals can be scored across the lifespan. Overall, the capacity to generate reliable lifespan and physiological data from the NemaLife chip underscores the potential of this device to accelerate healthspan and lifespan investigations in C. elegans.

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High-throughput imaging of Caenorhabditis elegans aging using collective activity monitoring

10.1101/2021.10.18.464905 ◽

2021 ◽

Author(s):

Anthony D Fouad ◽

Matthew A Churgin ◽

Julia Hayden ◽

Joyce Xu ◽

Jeong-Inn Park ◽

...

Keyword(s):

Large Scale ◽

Imaging System ◽

Activity Monitoring ◽

Automated System ◽

Aging Research ◽

C Elegans ◽

Collective Activity ◽

Large Numbers ◽

Natural Isolates ◽

Rate Of Decline

The genetic manipulability and short lifespan of C. elegans make it an important model for aging research. Widely applied methods for measurements of worm aging based on manual observation are labor intensive and low-throughput. Here, we describe the Worm Collective Activity Monitoring Platform (WormCamp), a system for assaying aging in C. elegans by monitoring activity of populations of worms in standard 24-well plates. We show that metrics based on the rate of decline in collective activity can be used to estimate the average lifespan and locomotor healthspan in the population. Using the WormCamp, we assay a panel of highly divergent natural isolates of C. elegans and show that both lifespan and locomotor healthspan display substantial heritability. To facilitate analysis of large numbers of worms, we developed a robotic imaging system capable of simultaneous automated monitoring of activity, lifespan, and locomotor healthspan in up to 2,304 populations containing a total of ~90,000 animals. We applied the automated system to conduct a large-scale RNA interference screen for genes that affect lifespan and locomotor healthspan. The WormCamp system is complementary to other current automated methods for assessing C. elegans aging and is well suited for efficiently screening large numbers of conditions.

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A robotic system for high-throughput automated lifespan and phenotyping analysis in C. elegans

Innovation in Aging ◽

10.1093/geroni/igaa057.3270 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

pp. 886-886

Author(s):

Elena Vayndorf ◽

Jason Pitt ◽

Judy Wu ◽

Emily Chang ◽

Richard Nguyen ◽

...

Keyword(s):

High Throughput ◽

Large Scale ◽

Nematode Species ◽

Robotic System ◽

Model Organisms ◽

Biological Aging ◽

Digital Cameras ◽

C Elegans ◽

Age Related ◽

3D Printers

Abstract A goal of gerontology-related research is to develop therapies to improve the healthy period of life by understanding and targeting the molecular hallmarks of biological aging. Much progress has been made toward understanding the genetic and biochemical nature of these hallmarks through studies using simple invertebrate model organisms, such as the nematode Caenorhabditis elegans. Over the past decade, the identification of potential genetic and pharmacological modifiers of lifespan and age-related pathologies in C. elegans and other model organisms has yielded fruitful leads for follow-up investigation. However, such studies are typically time- consuming and labor-intensive. The goal of our work is to automate tasks that require frequent, repeated observations and hours of manual labor to collect and analyze lifespan, motility, and other behavioral data in C. elegans and other nematode models. The advent of affordable high-quality digital cameras, robotics systems, and 3D printers, as well as the decreasing financial and computational costs of image storage and processing, have allowed us to automate data capture and analysis on a large scale. To this end, our group recently developed a tool, we call the WormBot, consisting of an unbiased, high-throughput, automated robotic system and corresponding software, to perform genetic and pharmacological quantification of lifespan and health measures in C. elegans and related nematode species. We will report updates recently made to this system, including significant improvements to hardware, and present screening results from proteasome stimulator drugs known to reduce the accumulation of proteotoxic proteins linked to neurodegenerative diseases and aging.

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Clinical, pathological and genetic spectrum in 89 cases of mitochondrial progressive external ophthalmoplegia

Journal of Medical Genetics ◽

10.1136/jmedgenet-2019-106649 ◽

2020 ◽

Vol 57 (9) ◽

pp. 643-646 ◽

Cited By ~ 1

Author(s):

Claudia Rodríguez-López ◽

Luis M. García-Cárdaba ◽

Alberto Blázquez ◽

Pablo Serrano-Lorenzo ◽

Gerardo Gutiérrez-Gutiérrez ◽

...

Keyword(s):

Muscle Biopsy ◽

Large Scale ◽

Genetic Disorders ◽

Genetic Diagnosis ◽

Diagnostic Algorithm ◽

Progressive External Ophthalmoplegia ◽

Mtdna Mutations ◽

Mtdna Deletions ◽

Genetic Features ◽

Mtdna Deletion

BackgroundMitochondrial progressive external ophthalmoplegia (PEO) encompasses a broad spectrum of clinical and genetic disorders. We describe the phenotypic subtypes of PEO and its correlation with molecular defects and propose a diagnostic algorithm.MethodsRetrospective analysis of the clinical, pathological and genetic features of 89 cases.ResultsThree main phenotypes were found: ‘pure PEO’ (42%), consisting of isolated palpebral ptosis with ophthalmoparesis; Kearns-Sayre syndrome (10%); and ‘PEO plus’, which associates extraocular symptoms, distinguishing the following subtypes: : myopathic (33%), bulbar (12%) and others (3%). Muscle biopsy was the most accurate test, showing mitochondrial changes in 95%. Genetic diagnosis was achieved in 96% of the patients. Single large-scale mitochondrial DNA (mtDNA) deletion was the most frequent finding (63%), followed by multiple mtDNA deletions (26%) due to mutations in TWNK (n=8), POLG (n=7), TK2 (n=6) or RRM2B (n=2) genes, and point mtDNA mutations (7%). Three new likely pathogenic mutations were identified in the TWNK and MT-TN genes.ConclusionsPhenotype–genotype correlations cannot be brought in mitochondrial PEO. Muscle biopsy should be the first step in the diagnostic flow of PEO when mitochondrial aetiology is suspected since it also enables the study of mtDNA rearrangements. If no mtDNA deletions are identified, whole mtDNA sequencing should be performed.

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Regulation of defective mitochondrial DNA accumulation and transmission in C. elegans by the programmed cell death and aging pathways

10.1101/2021.10.27.466108 ◽

2021 ◽

Author(s):

Sagen E Flowers ◽

Rushali Kothari ◽

Yamila N Torres Cleuren ◽

Melissa R Alcorn ◽

Chee Kiang Ewe ◽

...

Keyword(s):

Quality Control ◽

Purifying Selection ◽

Mitochondrial Genomes ◽

Older Mothers ◽

C Elegans ◽

Age Related ◽

Age Dependent ◽

Mtdna Deletion ◽

Selection Mechanisms ◽

Dependent Mechanism

The heteroplasmic state of eukaryotic cells allows for cryptic accumulation of defective mitochondrial genomes (mtDNA). Purifying selection mechanisms operate to remove such dysfunctional mtDNAs. We found that pro-apoptotic regulators, including the CED-3 and CSP-1 caspases, the BH3-only protein CED-13, and PCD corpse engulfment factors, are required in C. elegans to attenuate germline abundance of a 3.1 kb mtDNA deletion mutation, uaDf5, which is normally stably maintained in heteroplasmy with wildtype mtDNA. In contrast, removal of CED-4/Apaf1 or a mutation in the CED-4-interacting prodomain of CED-3, do not increase accumulation of the defective mtDNA, suggesting induction of a non-canonical germline PCD mechanism or non-apoptotic action of the CED-13/caspase axis. We also found that the abundance of germline mtDNAuaDf5 reproducibly increases with age of the mothers. This effect is transmitted to the offspring of older mothers, with only partial intergenerational removal of the defective mtDNA. In mutants with elevated mtDNAuaDf5 levels, this removal is enhanced in older mothers, suggesting an age-dependent mechanism of mtDNA quality control. Indeed, we found that both steady-state and age-related accumulation rates of uaDf5 are markedly decreased in long-lived, and increased in short-lived, mutants. These findings reveal that regulators of both PCD and aging are required for germline mtDNA quality control and its intergenerational transmission.

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Immigrant Youth in Germany

European Psychologist ◽

10.1027/1016-9040/a000154 ◽

2013 ◽

Vol 18 (3) ◽

pp. 158-168 ◽

Cited By ~ 28

Author(s):

Emily Frankenberg ◽

Katharina Kupper ◽

Ruth Wagner ◽

Stephan Bongard

Keyword(s):

School System ◽

Large Scale ◽

Age Groups ◽

Well Being ◽

Ethnic Discrimination ◽

Emotional And Behavioral Problems ◽

Sociocultural Adaptation ◽

Age Related ◽

German School ◽

Transcultural Adaptation

This paper reviews research on young migrants in Germany. Particular attention is given to the question of how Germany’s history of migration, immigration policies, and public attitude toward migrants influence the transcultural adaptation of children and adolescents from different ethnic backgrounds. We combine past research with the results of new empirical studies in order to shed light on migrants’ psychological and sociocultural adaptation. Studies comparing young migrants and their German peers in terms of psychological well-being, life satisfaction, and mental health outcome suggest higher rates of emotional and behavioral problems among migrants of most age groups. With regard to adolescent populations between the ages of 14 and 17 years, however, the existence of differences between migrants and natives appears to be less clear. Research has also yielded inconsistent findings regarding the time trajectory of transcultural adaptation among adolescents. The coincidence of acculturation and age-related change is discussed as a possible source of these inconsistencies. Further, we provide an overview of risk and protective factors such as conflicting role expectations and ethnic discrimination, which may cause heightened vulnerability to adverse adaptation outcomes in some groups. Large-scale studies have repeatedly shown migrants of all age groups to be less successful within the German school system, indicating poor sociocultural adaptation. Possible explanations, such as the idiosyncrasies of the German school system, are presented. Our own studies contribute to the understanding of young migrants’ adaptation process by showing that it is their orientation to German culture, rather than the acculturation strategy of integration, that leads to the most positive psychological and sociocultural outcomes. The paper concludes by discussing implications for future cross-cultural research on young migrants and by suggesting recommendations for multicultural policies.

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Towards Control of an Estuary

Water Science & Technology ◽

10.2166/wst.1987.0077 ◽

1987 ◽

Vol 19 (9) ◽

pp. 155-174

Author(s):

Henk L. F. Saeijs

Keyword(s):

Shallow Water ◽

Storm Surge ◽

Salt Marshes ◽

Large Scale ◽

Western Europe ◽

Oxygen Depletion ◽

Negative Effects ◽

Intertidal Flats ◽

Environmental Consequences ◽

Short Time

The Delta Project is in its final stage. In 1974 it was subjected to political reconsideration, but it is scheduled now for completion in 1987. The final touches are being put to the storm-surge barrier and two compartment dams that divide the Oosterschelde into three areas: one tidal, one with reduced tide, and one a freshwater lake. Compartmentalization will result in 13% of channels, 45% of intertidal flats and 59% of salt marshes being lost. There is a net gain of 7% of shallow-water areas. Human interventions with large scale impacts are not new in the Oosterschelde but the large scale and short time in which these interventions are taking place are, as is the creation of a controlled tidal system. This article focusses on the area with reduced tide and compares resent day and expected characteristics. In this reduced tidal part salt marshes will extend by 30–70%; intertidal flats will erode to a lower level and at their edges, and the area of shallow water will increase by 47%. Biomass production on the intertidal flats will decrease, with consequences for crustaceans, fishes and birds. The maximum number of waders counted on one day and the number of ‘bird-days' will decrease drastically, with negative effects for the wader populations of western Europe. The net area with a hard substratum in the reduced tidal part has more than doubled. Channels will become shallower. Detritus import will not change significantly. Stratification and oxygen depletion will be rare and local. The operation of the storm-surge barrier and the closure strategy chosen are very important for the ecosystem. Two optional closure strategies can be followed without any additional environmental consequences. It was essential to determine a clearly defined plan of action for the whole area, and to make land-use choices from the outset. How this was done is briefly described.

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Modeling Extinction

10.1093/oso/9780195159455.001.0001 ◽

2003 ◽

Author(s):

M. E. J. Newman ◽

R. G. Palmer

Keyword(s):

Evolutionary Biology ◽

Large Scale ◽

Competitive Exclusion ◽

Applied Mathematics ◽

Santa Fe ◽

New Approach ◽

Self Organized ◽

Self Organized Criticality ◽

Extinction Events ◽

Mass Extinction Events

Developed after a meeting at the Santa Fe Institute on extinction modeling, this book comments critically on the various modeling approaches. In the last decade or so, scientists have started to examine a new approach to the patterns of evolution and extinction in the fossil record. This approach may be called "statistical paleontology," since it looks at large-scale patterns in the record and attempts to understand and model their average statistical features, rather than their detailed structure. Examples of the patterns these studies examine are the distribution of the sizes of mass extinction events over time, the distribution of species lifetimes, or the apparent increase in the number of species alive over the last half a billion years. In attempting to model these patterns, researchers have drawn on ideas not only from paleontology, but from evolutionary biology, ecology, physics, and applied mathematics, including fitness landscapes, competitive exclusion, interaction matrices, and self-organized criticality. A self-contained review of work in this field.

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Population Genetics ofCaenorhabditis elegans: The Paradox of Low Polymorphism in a Widespread Species

Genetics ◽

10.1093/genetics/163.1.147 ◽

2003 ◽

Vol 163 (1) ◽

pp. 147-157 ◽

Cited By ~ 6

Author(s):

Arjun Sivasundar ◽

Jody Hey

Keyword(s):

Genetic Variation ◽

Microsatellite Loci ◽

Population Expansion ◽

Widespread Species ◽

C Elegans ◽

Model Research ◽

The World ◽

Natural Isolates ◽

History Of ◽

Low Levels

AbstractCaenorhabditis elegans has become one of the most widely used model research organisms, yet we have little information on evolutionary processes and recent evolutionary history of this widespread species. We examined patterns of variation at 20 microsatellite loci in a sample of 23 natural isolates of C. elegans from various parts of the world. One-half of the loci were monomorphic among all strains, and overall genetic variation at microsatellite loci was low, relative to most other species. Some population structure was detected, but there was no association between the genetic and geographic distances among different natural isolates. Thus, despite the nearly worldwide occurrence of C. elegans, little evidence was found for local adaptation in strains derived from different parts of the world. The low levels of genetic variation within and among populations suggest that recent colonization and population expansion might have occurred. However, the patterns of variation are not consistent with population expansion. A possible explanation for the observed patterns is the action of background selection to reduce polymorphism, coupled with ongoing gene flow among populations worldwide.

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