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

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.

scholarly journals Age-Dependent Decline of NAD+ - Universal Truth or Confounded Consensus?

Nutrients ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 101
Author(s):  
A. Augusto Peluso ◽  
Mads V. Damgaard ◽  
Marcelo A. S. Mori ◽  
Jonas T. Treebak
Keyword(s):  
Nicotinamide Adenine Dinucleotide ◽  
Electron Transport Chain ◽  
Cell Type ◽  
Nad Metabolism ◽  
C Elegans ◽  
Age Related ◽  
Transport Chain ◽  
Age Dependent ◽  
Metabolic Reactions ◽  
Universal Truth

Nicotinamide adenine dinucleotide (NAD+) is an essential molecule involved in various metabolic reactions, acting as an electron donor in the electron transport chain and as a co-factor for NAD+-dependent enzymes. In the early 2000s, reports that NAD+ declines with aging introduced the notion that NAD+ metabolism is globally and progressively impaired with age. Since then, NAD+ became an attractive target for potential pharmacological therapies aiming to increase NAD+ levels to promote vitality and protect against age-related diseases. This review summarizes and discusses a collection of studies that report the levels of NAD+ with aging in different species (i.e., yeast, C. elegans, rat, mouse, monkey, and human), to determine whether the notion that overall NAD+ levels decrease with aging stands true. We find that, despite systematic claims of overall changes in NAD+ levels with aging, the evidence to support such claims is very limited and often restricted to a single tissue or cell type. This is particularly true in humans, where the development of NAD+ levels during aging is still poorly characterized. There is a need for much larger, preferably longitudinal, studies to assess how NAD+ levels develop with aging in various tissues. This will strengthen our conclusions on NAD metabolism during aging and should provide a foundation for better pharmacological targeting of relevant tissues.

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

2019 ◽  
Vol 59 (4) ◽  
pp. 983-993 ◽  
Author(s):  
Jennifer A Sullins ◽  
Anna L Coleman-Hulbert ◽  
Alexandra Gallegos ◽  
Dana K Howe ◽  
Dee R Denver ◽  
...  
Keyword(s):  
Evolutionary Biology ◽  
Large Scale ◽  
C Elegans ◽  
Mtdna Mutations ◽  
Age Related ◽  
Selfish Element ◽  
Mtdna Deletion ◽  
Natural Isolates ◽  
Compensatory Mutations ◽  
Short Time

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.

scholarly journals Irving S. Wright Award: Cellular recycling in aging and disease: The importance of taking out the trash

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 386-386
Author(s):  
Malene Hansen
Keyword(s):  
Quality Control ◽  
Normal Aging ◽  
Recycling Process ◽  
C Elegans ◽  
Control Processes ◽  
Age Related ◽  
Round Worm ◽  
And Function

Abstract Aging is greatly influenced by quality-control processes that keep the materials inside our cells in proper shape and function. One of these processes is called autophagy, which means "self-eating". This cellular recycling process can digest damaged components to provide new and better parts for the cell. Autophagy plays important roles in many age-related diseases and has been directly linked to aging. In our laboratory, we use the microscopic soil-dwelling round worm C. elegans to understand how autophagy is linked to aging and disease. In this Wright Award seminar, I will discuss our progress on understanding how autophagy is regulated during normal aging and how it may promote a long and healthy lifespan.

scholarly journals Age-Dependent Decline of NAD+ - Universal Truth or Confounded Consensus?

2021 ◽  
Author(s):  
Augusto Peluso ◽  
Mads Vargas Damgaard ◽  
Marcelo Alves Mori ◽  
Jonas Thue Treebak
Keyword(s):  
Nicotinamide Adenine Dinucleotide ◽  
Electron Transport Chain ◽  
Cell Type ◽  
Nad Metabolism ◽  
C Elegans ◽  
Age Related ◽  
Transport Chain ◽  
Age Dependent ◽  
Metabolic Reactions ◽  
Universal Truth

Nicotinamide adenine dinucleotide (NAD+) is an essential molecule involved in various metabolic reactions, acting as an electron donor in the electron transport chain and as a co-factor for NAD+-dependent enzymes. In the early 2000s, reports that NAD+ declines with aging introduced the notion that NAD+ metabolism is globally and progressively impaired with time. Since then, NAD+ became an attractive target for potential pharmacological therapies aiming to boost NAD+ levels to promote vitality and protect against age-related diseases. This review summarizes and discusses a collection of studies that report the levels of NAD+ with aging in different species (i.e., yeast, C. elegans, rat, mouse, monkey, and human) to determine whether the notion that overall NAD+ levels decrease with aging stands true. We find that despite systematic claims of overall changes in NAD+ levels with aging, the evidence to support it is very limited and often restricted to a single tissue or cell type. This is particularly true in humans, where the development of NAD+ levels during aging is still poorly characterized. There is a need for much larger, preferably longitudinal, studies aimed to assess how NAD+ levels develop with aging in various tissues. This will strengthen our conclusions on NAD+ during aging and should provide a foundation for better pharmacological targeting of relevant tissues.

scholarly journals Two human metabolites rescue a C. elegans model of Alzheimer’s disease via a cytosolic unfolded protein response

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Priyanka Joshi ◽  
Michele Perni ◽  
Ryan Limbocker ◽  
Benedetta Mannini ◽  
Sam Casford ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Unfolded Protein Response ◽  
Neurodegenerative Disorders ◽  
C Elegans ◽  
Unfolded Protein ◽  
Model Of Alzheimer’S Disease ◽  
Age Related ◽  
Parkinson’S Diseases ◽  
Protein Response

AbstractAge-related changes in cellular metabolism can affect brain homeostasis, creating conditions that are permissive to the onset and progression of neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. Although the roles of metabolites have been extensively studied with regard to cellular signaling pathways, their effects on protein aggregation remain relatively unexplored. By computationally analysing the Human Metabolome Database, we identified two endogenous metabolites, carnosine and kynurenic acid, that inhibit the aggregation of the amyloid beta peptide (Aβ) and rescue a C. elegans model of Alzheimer’s disease. We found that these metabolites act by triggering a cytosolic unfolded protein response through the transcription factor HSF-1 and downstream chaperones HSP40/J-proteins DNJ-12 and DNJ-19. These results help rationalise previous observations regarding the possible anti-ageing benefits of these metabolites by providing a mechanism for their action. Taken together, our findings provide a link between metabolite homeostasis and protein homeostasis, which could inspire preventative interventions against neurodegenerative disorders.

scholarly journals The Age-Sensitive Efficacy of Calorie Restriction on Mitochondrial Biogenesis and mtDNA Damage in Rat Liver

2021 ◽  
Vol 22 (4) ◽  
pp. 1665
Author(s):  
Guglielmina Chimienti ◽  
Anna Picca ◽  
Flavio Fracasso ◽  
Francesco Russo ◽  
Antonella Orlando ◽  
...  
Keyword(s):  
Calorie Restriction ◽  
Citrate Synthase ◽  
Aging Effect ◽  
Mtdna Damage ◽  
Mitochondrial Markers ◽  
Age Related ◽  
Efficacious Treatment ◽  
Mtdna Deletion ◽  
Cyt C ◽  
Ad Libitum

Calorie restriction (CR) is the most efficacious treatment to delay the onset of age-related changes such as mitochondrial dysfunction. However, the sensitivity of mitochondrial markers to CR and the age-related boundaries of CR efficacy are not fully elucidated. We used liver samples from ad libitum-fed (AL) rats divided in: 18-month-old (AL-18), 28-month-old (AL-28), and 32-month-old (AL-32) groups, and from CR-treated (CR) 28-month-old (CR-28) and 32-month-old (CR-32) counterparts to assay the effect of CR on several mitochondrial markers. The age-related decreases in citrate synthase activity, in TFAM, MFN2, and DRP1 protein amounts and in the mtDNA content in the AL-28 group were prevented in CR-28 counterparts. Accordingly, CR reduced oxidative mtDNA damage assessed through the incidence of oxidized purines at specific mtDNA regions in CR-28 animals. These findings support the anti-aging effect of CR up to 28 months. Conversely, the protein amounts of LonP1, Cyt c, OGG1, and APE1 and the 4.8 Kb mtDNA deletion content were not affected in CR-28 rats. The absence of significant differences between the AL-32 values and the CR-32 counterparts suggests an age-related boundary of CR efficacy at this age. However, this only partially curtails the CR benefits in counteracting the generalized aging decline and the related mitochondrial involvement.

scholarly journals Crosstalk between Different DNA Repair Pathways Contributes to Neurodegenerative Diseases

Biology ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 163
Author(s):  
Swapnil Gupta ◽  
Panpan You ◽  
Tanima SenGupta ◽  
Hilde Nilsen ◽  
Kulbhushan Sharma
Keyword(s):  
Dna Repair ◽  
Neurodegenerative Diseases ◽  
3D Models ◽  
Model Systems ◽  
Spinocerebellar Ataxias ◽  
C Elegans ◽  
Cellular Processes ◽  
Age Related ◽  
Damage Response ◽  
Lateral Sclerosis

Genomic integrity is maintained by DNA repair and the DNA damage response (DDR). Defects in certain DNA repair genes give rise to many rare progressive neurodegenerative diseases (NDDs), such as ocular motor ataxia, Huntington disease (HD), and spinocerebellar ataxias (SCA). Dysregulation or dysfunction of DDR is also proposed to contribute to more common NDDs, such as Parkinson’s disease (PD), Alzheimer’s disease (AD), and Amyotrophic Lateral Sclerosis (ALS). Here, we present mechanisms that link DDR with neurodegeneration in rare NDDs caused by defects in the DDR and discuss the relevance for more common age-related neurodegenerative diseases. Moreover, we highlight recent insight into the crosstalk between the DDR and other cellular processes known to be disturbed during NDDs. We compare the strengths and limitations of established model systems to model human NDDs, ranging from C. elegans and mouse models towards advanced stem cell-based 3D models.

scholarly journals Not Frozen in the Ice: large and Dynamic Rearrangements in the Mitochondrial Genomes of the Antarctic Fish

2021 ◽  
Author(s):  
Chiara Papetti ◽  
Massimiliano Babbucci ◽  
Agnes Dettai ◽  
Andrea Basso ◽  
Magnus Lucassen ◽  
...  
Keyword(s):  
Gene Order ◽  
Hot Spot ◽  
Mitochondrial Gene ◽  
Antarctic Fish ◽  
Purifying Selection ◽  
Compositional Bias ◽  
Mitochondrial Genomes ◽  
Notothenioid Fish ◽  
Antarctic Notothenioids ◽  
The Antarctic

Abstract The vertebrate mitochondrial genomes generally present a typical gene order. Exceptions are uncommon and important to study the genetic mechanisms of gene order rearrangements and their consequences on phylogenetic output and mitochondrial function. Antarctic notothenioid fish carry some peculiar rearrangements of the mitochondrial gene order. In this first systematic study of 28 species, we analysed known and undescribed mitochondrial genome rearrangements for a total of eight different gene orders within the notothenioid fish. Our reconstructions suggest that transpositions, duplications and inversion of multiple genes are the most likely mechanisms of rearrangement in notothenioid mitochondrial genomes. In Trematominae, we documented an extremely rare inversion of a large genomic segment of 5300 bp that partially affected the gene compositional bias but not the phylogenetic output. The genomic region delimited by nad5 and trnF, close to the area of the Control Region, was identified as the hot spot of variation in Antarctic fish mitochondrial genomes. Analysing the sequence of several intergenic spacers and mapping the arrangements on a newly generated phylogeny showed that the entire history of the Antarctic notothenioids is characterized by multiple, relatively rapid, events of disruption of the gene order. We hypothesised that a pre-existing genomic flexibility of the ancestor of the Antarctic notothenioids may have generated a precondition for gene order rearrangement, and the pressure of purifying selection could have worked for a rapid restoration of the mitochondrial functionality and compactness after each event of rearrangement.

scholarly journals Steroid hormones sulfatase inactivation extends lifespan and ameliorates age-related diseases

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Mercedes M. Pérez-Jiménez ◽  
José M. Monje-Moreno ◽  
Ana María Brokate-Llanos ◽  
Mónica Venegas-Calerón ◽  
Alicia Sánchez-García ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Caenorhabditis Elegans ◽  
Protein Aggregation ◽  
Steroid Hormones ◽  
Sensory Neurons ◽  
Environmental Cues ◽  
Steroid Sulfatase ◽  
Loss Of Function ◽  
C Elegans ◽  
Age Related

AbstractAging and fertility are two interconnected processes. From invertebrates to mammals, absence of the germline increases longevity. Here we show that loss of function of sul-2, the Caenorhabditis elegans steroid sulfatase (STS), raises the pool of sulfated steroid hormones, increases longevity and ameliorates protein aggregation diseases. This increased longevity requires factors involved in germline-mediated longevity (daf-16, daf-12, kri-1, tcer-1 and daf-36 genes) although sul-2 mutations do not affect fertility. Interestingly, sul-2 is only expressed in sensory neurons, suggesting a regulation of sulfated hormones state by environmental cues. Treatment with the specific STS inhibitor STX64, as well as with testosterone-derived sulfated hormones reproduces the longevity phenotype of sul-2 mutants. Remarkably, those treatments ameliorate protein aggregation diseases in C. elegans, and STX64 also Alzheimer’s disease in a mammalian model. These results open the possibility of reallocating steroid sulfatase inhibitors or derivates for the treatment of aging and aging related diseases.

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