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https://www.readbyqxmd.com/read/28658230/many-possible-maximum-lifespan-trajectories
#1
Bryan G Hughes, Siegfried Hekimi
No abstract text is available yet for this article.
June 28, 2017: Nature
https://www.readbyqxmd.com/read/28441527/proteostasis-or-aging-let-the-chips-fall-where-they-may
#2
REVIEW
Robyn Branicky, Siegfried Hekimi
The conserved E3 ubiquitin ligase CHIP/CHN-1 contributes to proteostasis by ubiquitylating HSP70 and HSP90-interacting proteins. In a recent issue of Cell,Tawo et al. (2017) show that CHIP/CHN-1 also directly ubiquitylates the insulin receptor INSR/DAF-2 to regulate its turnover. These findings suggest an unexpected interpretation of the effects of altered proteostasis on survival.
April 24, 2017: Developmental Cell
https://www.readbyqxmd.com/read/28409910/pathogenicity-of-two-coq7-mutations-and-responses-to-2-4-dihydroxybenzoate-bypass-treatment
#3
Ying Wang, Christopher Smith, Jillian S Parboosingh, Aneal Khan, Micheil Innes, Siegfried Hekimi
Primary ubiquinone (co-enzyme Q) deficiency results in a wide range of clinical features due to mitochondrial dysfunction. Here, we analyse and characterize two mutations in the ubiquinone biosynthetic gene COQ7. One mutation from the only previously identified patient (V141E), and one (L111P) from a 6-year-old girl who presents with spasticity and bilateral sensorineural hearing loss. We used patient fibroblast cell lines and a heterologous expression system to show that both mutations lead to loss of protein stability and decreased levels of ubiquinone that correlate with the severity of mitochondrial dysfunction...
October 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/28404998/a-single-biochemical-activity-underlies-the-pleiotropy-of-the-aging-related-protein-clk-1
#4
Ju-Ling Liu, Callista Yee, Ying Wang, Siegfried Hekimi
The Caenorhabditis elegans clk-1 gene and the orthologous mouse gene Mclk1 encode a mitochondrial hydroxylase that is necessary for the biosynthesis of ubiquinone (UQ). Mutations in these genes produce broadly pleiotropic phenotypes in both species, including a lengthening of animal lifespan. A number of features of the C. elegans clk-1 mutants, including a maternal effect, particularly extensive pleiotropy, as well as unexplained differences between alleles have suggested that CLK-1/MCLK1 might have additional functions besides that in UQ biosynthesis...
April 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28068429/functional-requirements-for-heparan-sulfate-biosynthesis-in-morphogenesis-and-nervous-system-development-in-c-elegans
#5
Cassandra R Blanchette, Andrea Thackeray, Paola N Perrat, Siegfried Hekimi, Claire Y Bénard
The regulation of cell migration is essential to animal development and physiology. Heparan sulfate proteoglycans shape the interactions of morphogens and guidance cues with their respective receptors to elicit appropriate cellular responses. Heparan sulfate proteoglycans consist of a protein core with attached heparan sulfate glycosaminoglycan chains, which are synthesized by glycosyltransferases of the exostosin (EXT) family. Abnormal HS chain synthesis results in pleiotropic consequences, including abnormal development and tumor formation...
January 2017: PLoS Genetics
https://www.readbyqxmd.com/read/27683586/mitochondrial-ros-and-the-effectors-of-the-intrinsic-apoptotic-pathway-in-aging-cells-the-discerning-killers
#6
REVIEW
Siegfried Hekimi, Ying Wang, Alycia Noë
It has become clear that mitochondrial reactive oxygen species (mtROS) are not simply villains and mitochondria the hapless targets of their attacks. Rather, it appears that mitochondrial dysfunction itself and the signaling function of mtROS can have positive effects on lifespan, helping to extend longevity. If events in the mitochondria can lead to better cellular homeostasis and better survival of the organism in ways beyond providing ATP and biosynthetic products, we can conjecture that they act on other cellular components through appropriate signaling pathways...
2016: Frontiers in Genetics
https://www.readbyqxmd.com/read/27683245/antioxidants-reveal-an-inverted-u-shaped-dose-response-relationship-between-reactive-oxygen-species-levels-and-the-rate-of-aging-in-caenorhabditis-elegans
#7
David Desjardins, Briseida Cacho-Valadez, Ju-Ling Liu, Ying Wang, Callista Yee, Kristine Bernard, Arman Khaki, Lionel Breton, Siegfried Hekimi
Reactive oxygen species (ROS) are potentially toxic, but they are also signaling molecules that modulate aging. Recent observations that ROS can promote longevity have to be reconciled with the numerous claims about the benefits of antioxidants on lifespan. Here, three antioxidants [N-acetylcysteine (NAC), vitamin C, and resveratrol (RSV)] were tested on Caenorhabditis elegans mutants that alter drug uptake, mitochondrial function, and ROS metabolism. We observed that like pro-oxidants, antioxidants can both lengthen and shorten lifespan, dependent on concentration, genotypes, and conditions...
February 2017: Aging Cell
https://www.readbyqxmd.com/read/27638422/different-mechanisms-of-longevity-in-long-lived-mouse-and-caenorhabditis-elegans-mutants-revealed-by-statistical-analysis-of-mortality-rates
#8
Bryan G Hughes, Siegfried Hekimi
Mouse and Caenorhabditis elegans mutants with altered life spans are being used to investigate the aging process and how genes determine life span. The survival of a population can be modeled by the Gompertz function, which comprises two parameters. One of these parameters ("G") describes the rate at which mortality accelerates with age and is often described as the "rate of aging." The other parameter ("A") may correspond to the organism's baseline vulnerability to deleterious effects of disease and the environment...
November 2016: Genetics
https://www.readbyqxmd.com/read/26827090/understanding-ubiquinone
#9
REVIEW
Ying Wang, Siegfried Hekimi
Ubiquinone (UQ; also known as coenzyme Q; CoQ) is a mobile component of the mitochondrial electron transport chain, where it acts as a pro-oxidant in its ubisemiquinone state. Despite this, UQ is also believed to be a membrane antioxidant. These properties place UQ at the center of hotly debated questions about how mitochondria and reactive oxygen species (ROS) impact aging and disease. New studies using transgenic mouse models have provided unexpected insights into whether, and how, UQ is required in various processes, cell types, and subcellular locations...
May 2016: Trends in Cell Biology
https://www.readbyqxmd.com/read/26785479/mitochondrial-dysfunction-and-longevity-in-animals-untangling-the-knot
#10
REVIEW
Ying Wang, Siegfried Hekimi
Mitochondria generate adenosine 5'-triphosphate (ATP) and are a source of potentially toxic reactive oxygen species (ROS). It has been suggested that the gradual mitochondrial dysfunction that is observed to accompany aging could in fact be causal to the aging process. Here we review findings that suggest that age-dependent mitochondrial dysfunction is not sufficient to limit life span. Furthermore, mitochondrial ROS are not always deleterious and can even stimulate pro-longevity pathways. Thus, mitochondrial dysfunction plays a complex role in regulating longevity...
December 4, 2015: Science
https://www.readbyqxmd.com/read/26111777/coenzyme-q10-restores-oocyte-mitochondrial-function-and-fertility-during-reproductive-aging
#11
Assaf Ben-Meir, Eliezer Burstein, Aluet Borrego-Alvarez, Jasmine Chong, Ellen Wong, Tetyana Yavorska, Taline Naranian, Maggie Chi, Ying Wang, Yaakov Bentov, Jennifer Alexis, James Meriano, Hoon-Ki Sung, David L Gasser, Kelle H Moley, Siegfried Hekimi, Robert F Casper, Andrea Jurisicova
Female reproductive capacity declines dramatically in the fourth decade of life as a result of an age-related decrease in oocyte quality and quantity. The primary causes of reproductive aging and the molecular factors responsible for decreased oocyte quality remain elusive. Here, we show that aging of the female germ line is accompanied by mitochondrial dysfunction associated with decreased oxidative phosphorylation and reduced Adenosine tri-phosphate (ATP) level. Diminished expression of the enzymes responsible for CoQ production, Pdss2 and Coq6, was observed in oocytes of older females in both mouse and human...
October 2015: Aging Cell
https://www.readbyqxmd.com/read/25744659/mitochondrial-function-and-lifespan-of-mice-with-controlled-ubiquinone-biosynthesis
#12
Ying Wang, Daniella Oxer, Siegfried Hekimi
Ubiquinone (UQ) is implicated in mitochondrial electron transport, superoxide generation and as a membrane antioxidant. Here we present a mouse model in which UQ biosynthesis can be interrupted and partially restored at will. Global loss of UQ leads to gradual loss of mitochondrial function, gradual development of disease phenotypes and shortened lifespan. However, we find that UQ does not act as antioxidant in vivo and that its requirement for electron transport is much lower than anticipated, even in vital mitochondria-rich organs...
March 6, 2015: Nature Communications
https://www.readbyqxmd.com/read/25744157/a-microfluidic-device-for-efficient-chemical-testing-using-caenorhabditis-elegans
#13
Pengfei Song, Weize Zhang, Alexandre Sobolevski, Kristine Bernard, Siegfried Hekimi, Xinyu Liu
The nematode worm Caenorhabditis elegans has been employed as a popular model organism in many fields of biological research. In this paper, we present a microfluidic device for facilitating chemical testing using C. elegans. For testing chemicals on chip, the device houses single nematodes in microfluidic chambers and precisely adjusts the chamber's chemical environment during experiments. Eight nematodes can be readily loaded into the chambers through separate loading channels in a quick and gentle manner...
April 2015: Biomedical Microdevices
https://www.readbyqxmd.com/read/25671321/mitochondrial-and-cytoplasmic-ros-have-opposing-effects-on-lifespan
#14
Claire E Schaar, Dylan J Dues, Katie K Spielbauer, Emily Machiela, Jason F Cooper, Megan Senchuk, Siegfried Hekimi, Jeremy M Van Raamsdonk
Reactive oxygen species (ROS) are highly reactive, oxygen-containing molecules that can cause molecular damage within the cell. While the accumulation of ROS-mediated damage is widely believed to be one of the main causes of aging, ROS also act in signaling pathways. Recent work has demonstrated that increasing levels of superoxide, one form of ROS, through treatment with paraquat, results in increased lifespan. Interestingly, treatment with paraquat robustly increases the already long lifespan of the clk-1 mitochondrial mutant, but not other long-lived mitochondrial mutants such as isp-1 or nuo-6...
February 2015: PLoS Genetics
https://www.readbyqxmd.com/read/25413331/compensatory-elevation-of-voluntary-activity-in-mouse-mutants-with-impaired-mitochondrial-energy-metabolism
#15
Jérôme Lapointe, Bryan Hughes, Eve Bigras, Siegfried Hekimi
Mitochondria play a crucial role in determining whole-body metabolism and exercise capacity. Genetic mouse models of mild mitochondrial dysfunction provide an opportunity to understand how mitochondrial function affects these parameters. MCLK1 (a.k.a. Coq7) is an enzyme implicated in the biosynthesis of ubiquinone (UQ; Coenzyme Q). Low levels of MCLK1 in Mclk1(+/-) heterozygous mutants lead to abnormal sub-mitochondrial distribution of UQ, impaired mitochondrial function, elevated mitochondrial oxidative stress, and increased lifespan...
November 1, 2014: Physiological Reports
https://www.readbyqxmd.com/read/24813612/the-intrinsic-apoptosis-pathway-mediates-the-pro-longevity-response-to-mitochondrial-ros-in-c-elegans
#16
Callista Yee, Wen Yang, Siegfried Hekimi
The increased longevity of the C. elegans electron transport chain mutants isp-1 and nuo-6 is mediated by mitochondrial ROS (mtROS) signaling. Here we show that the mtROS signal is relayed by the conserved, mitochondria-associated, intrinsic apoptosis signaling pathway (CED-9/Bcl2, CED-4/Apaf1, and CED-3/Casp9) triggered by CED-13, an alternative BH3-only protein. Activation of the pathway by an elevation of mtROS does not affect apoptosis but protects from the consequences of mitochondrial dysfunction by triggering a unique pattern of gene expression that modulates stress sensitivity and promotes survival...
May 8, 2014: Cell
https://www.readbyqxmd.com/read/24586177/cep-1-the-caenorhabditis-elegans-p53-homolog-mediates-opposing-longevity-outcomes-in-mitochondrial-electron-transport-chain-mutants
#17
Aiswarya Baruah, Hsinwen Chang, Mathew Hall, Jie Yuan, Sarah Gordon, Erik Johnson, Ludmila L Shtessel, Callista Yee, Siegfried Hekimi, W Brent Derry, Siu Sylvia Lee
Caenorhabditis elegans CEP-1 and its mammalian homolog p53 are critical for responding to diverse stress signals. In this study, we found that cep-1 inactivation suppressed the prolonged lifespan of electron transport chain (ETC) mutants, such as isp-1 and nuo-6, but rescued the shortened lifespan of other ETC mutants, such as mev-1 and gas-1. We compared the CEP-1-regulated transcriptional profiles of the long-lived isp-1 and the short-lived mev-1 mutants and, to our surprise, found that CEP-1 regulated largely similar sets of target genes in the two mutants despite exerting opposing effects on their longevity...
February 2014: PLoS Genetics
https://www.readbyqxmd.com/read/24058856/the-impact-of-mitochondrial-oxidative-stress-on-bile-acid-like-molecules-in-c-elegans-provides-a-new-perspective-on-human-metabolic-diseases
#18
Ju-Ling Liu, Siegfried Hekimi
C. elegans is a model used to study cholesterol metabolism and the functions of its metabolites. Several studies have reported that, in worms, cholesterol is not a structural component of the membrane as it is in vertebrates. However, as in other animals, it is used for the synthesis of steroid hormones that regulate physiological processes such as dauer formation, molting and defecation. After cholesterol is taken up by the gut, mechanisms of transport of cholesterol between tissues in C. elegans involve lipoproteins, as in mammals...
January 1, 2013: Worm
https://www.readbyqxmd.com/read/23847050/mitochondrial-respiration-without-ubiquinone-biosynthesis
#19
Ying Wang, Siegfried Hekimi
Ubiquinone (UQ), a.k.a. coenzyme Q, is a redox-active lipid that participates in several cellular processes, in particular mitochondrial electron transport. Primary UQ deficiency is a rare but severely debilitating condition. Mclk1 (a.k.a. Coq7) encodes a conserved mitochondrial enzyme that is necessary for UQ biosynthesis. We engineered conditional Mclk1 knockout models to study pathogenic effects of UQ deficiency and to assess potential therapeutic agents for the treatment of UQ deficiencies. We found that Mclk1 knockout cells are viable in the total absence of UQ...
December 1, 2013: Human Molecular Genetics
https://www.readbyqxmd.com/read/23734326/enhanced-immunity-in-slowly-aging-mutant-mice-with-high-mitochondrial-oxidative-stress
#20
Siegfried Hekimi
The mitochondria of slowly aging Mclk1 (+/-) mutant mice produce high levels of reactive oxygen species (ROS). These animals display enhanced immune reactivity in response to lipopolysaccharide, Salmonella, and tumor-cell grafts, experience limited damage from these treatments and are partially protected from infection and tumorigenesis. We propose that the activation of the immune system by mitochondrial ROS reduces the rate of aging.
April 1, 2013: Oncoimmunology
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