Disruption of insulin signalling preserves bioenergetic competence of mitochondria in ageing Caenorhabditis elegans

Department of Biology, Ghent University, K L Ledeganckstraat 35, Ghent B-9000, Belgium. .
BMC Biology (Impact Factor: 7.98). 06/2010; 8(1):91. DOI: 10.1186/1741-7007-8-91
Source: PubMed


The gene daf-2 encodes the single insulin/insulin growth factor-1-like receptor of Caenorhabditis elegans. The reduction-of-function allele e1370 induces several metabolic alterations and doubles lifespan.
We found that the e1370 mutation alters aerobic energy production substantially. In wild-type worms the abundance of key mitochondrial proteins declines with age, accompanied by a dramatic decrease in energy production, although the mitochondrial mass, inferred from the mitochondrial DNA copy number, remains unaltered. In contrast, the age-dependent decrease of both key mitochondrial proteins and bioenergetic competence is considerably attenuated in daf-2(e1370) adult animals. The increase in daf-2(e1370) mitochondrial competence is associated with a higher membrane potential and increased reactive oxygen species production, but with little damage to mitochondrial protein or DNA. Together these results point to a higher energetic efficiency of daf-2(e1370) animals.
We conclude that low daf-2 function alters the overall rate of ageing by a yet unidentified mechanism with an indirect protective effect on mitochondrial function.

Download full-text


Available from: Filip Matthijssens,
  • Source
    • "In addition aging results in an increased size of lipid droplets (LD) as egg yolk lipoproteins continue to be produced after reproduction ceases (Herndon et al., 2002), and the appearance of enlarged dysfunctional mitochondria within cells (Gerstbrein et al., 2005). Accordingly, aged C. elegans experience a dramatic decline in mitochondrial oxygen consumption , and ATP and ADP content, starting as early as the onset of adulthood (Brys et al., 2010; Houthoofd et al., 2005). Aged C. elegans have also been shown to experience a loss of proteostasis and an accumulation of protein aggregates (David et al., 2010; Labbadia and Morimoto, 2014), as well as oxidatively damaged proteins and lipids (Ishii et al., 2002; Morcos et al., 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: To expand the understanding of aging in the model organism Caenorhabditis elegans, global quantification of metabolite and protein levels in young and aged nematodes was performed using mass spectrometry. With age, there was a decreased abundance of proteins functioning in transcription termination, mRNA degradation, mRNA stability, protein synthesis, and proteasomal function. Furthermore, there was altered S-adenosyl methionine metabolism as well as a decreased abundance of the S-adenosyl methionine synthetase (SAMS-1) protein. Other aging-related changes included alterations in free fatty acid levels and composition, decreased levels of ribosomal proteins, decreased levels of NADP-dependent isocitrate dehydrogenase (IDH1), a shift in the cellular redox state, an increase in sorbitol content, alterations in free amino acid levels, and indications of altered muscle function and sarcoplasmic reticulum Ca(2+) homeostasis. There were also decreases in pyrimidine and purine metabolite levels, most markedly nitrogenous bases. Supplementing the culture medium with cytidine (a pyrimidine nucleoside) or hypoxanthine (a purine base) increased lifespan slightly, suggesting that aging-induced alterations in ribonucleotide metabolism affect lifespan. An age-related increase in body size, lipotoxicity from ectopic yolk lipoprotein accumulation, a decline in NAD(+) levels, and mitochondrial electron transport chain dysfunction may explain many of these changes. In addition, dietary restriction in aged worms resulting from sarcopenia of the pharyngeal pump likely decreases the abundance of SAMS-1, possibly leading to decreased phosphatidylcholine levels, larger lipid droplets, and ER and mitochondrial stress. The complementary use of proteomics and metabolomics yielded unique insights into the molecular processes altered with age in C. elegans.
    Experimental gerontology 09/2015; 72. DOI:10.1016/j.exger.2015.09.013 · 3.49 Impact Factor
  • Source
    • "Age-related changes in mitochondrial metabolism are also well documented. Early life stages often display more anaerobic metabolism and spherical morphologies, and older individuals typically show signs of mitochondrial dysfunction although these effects are frequently tissue specific (Braeckman et al., 2002; Brand et al., 2004; Brys et al., 2007, 2010; Dillin et al., 2002; Hebert et al., 2010; Jansen and de Boer, 1998; Knudsen and Green, 2004; Meyer et al., 2007; Tsang and Lemire, 2003; Tsang et al., 2001; Yasuda et al., 2006). How reduced aerobic mitochondrial function will influence the effect of mitochondrial toxicants is not certain. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Enormous strides have recently been made in our understanding of the biology and pathobiology of mitochondria. Many diseases have been identified as caused by mitochondrial dysfunction, and many pharmaceuticals have been identified as previously unrecognized mitochondrial toxicants. A much smaller but growing literature indicates that mitochondria are also targeted by environmental pollutants. We briefly review the importance of mitochondrial function and maintenance for health based on the genetics of mitochondrial diseases and the toxicities resulting from pharmaceutical exposure. We then discuss how the principles of mitochondrial vulnerability illustrated by those fields might apply to environmental contaminants, with particular attention to factors that may modulate vulnerability including genetic differences, epigenetic interactions, tissue characteristics, and developmental stage. Finally, we review the literature related to environmental mitochondrial toxicants, with a particular focus on those toxicants that target mitochondrial DNA. We conclude that the fields of environmental toxicology and environmental health should focus more strongly on mitochondria.
    Toxicological Sciences 04/2013; 134(1). DOI:10.1093/toxsci/kft102 · 3.85 Impact Factor
  • Source
    • "Faced with hyperoxidative stress, organisms rely on antioxidant mechanisms to neutralize accumulating ROS. One method for microorganisms to prevent significant oxidation-induced damage is to generate antioxidant substances, such as vitamin E, oxalic acid, ascorbic acid and antioxidant enzymes such as superoxide dismutase [36], catalase, and peroxidase as well [32]. As the exudate that appeared on the surface of the sclerotia comprised oxalic acid [37]–[38] and antioxidant enzymes [31], these antioxidant molecules might play a part in resisting the hyperoxidant state. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Polyporus umbellatus sclerotia have been used as a diuretic agent in China for over two thousand years. A shortage of the natural P. umbellatus has prompted researchers to induce sclerotial formation in the laboratory. P. umbellatus cultivation in a sawdust-based substrate was investigated to evaluate the effect of low temperature conditions on sclerotial formation. A phenol-sulfuric acid method was employed to determine the polysaccharide content of wild P. umbellatus sclerotia and mycelia and sclerotia grown in low-temperature treatments. In addition, reactive oxygen species (ROS) content, expressed as the fluorescence intensity of mycelia during sclerotial differentiation was determined. Analysis of ROS generation and sclerotial formation in mycelia after treatment with the antioxidants such as diphenyleneiodonium chloride (DPI), apocynin (Apo), or vitamin C were studied. Furthermore, macroscopic and microscopic characteristics of sclerotial differentiation were observed. Sclerotia were not induced by continuous cultivation at 25°C. The polysaccharide content of the artificial sclerotia is 78% of that of wild sclerotia. In the low-temperature treatment group, the fluorescent intensity of ROS was higher than that of the room temperature (25°C) group which did not induce sclerotial formation all through the cultivation. The antioxidants DPI and Apo reduced ROS levels and did not induce sclerotial formation. Although the concentration-dependent effects of vitamin C (5-15 mg mL(-1)) also reduced ROS generation and inhibited sclerotial formation, using a low concentration of vitamin C (1 mg mL(-1)) successfully induced sclerotial differentiation and increased ROS production. Exposure to low temperatures induced P. umbellatus sclerotial morphogenesis during cultivation. Low temperature treatment enhanced ROS in mycelia, which may be important in triggering sclerotial differentiation in P. umbellatus. Moreover, the application of antioxidants impaired ROS generation and inhibited sclerotial formation. Our findings may help to provide new insights into the biological mechanisms underlying sclerotial morphogenesis in P. umbellatus.
    PLoS ONE 02/2013; 8(2):e56190. DOI:10.1371/journal.pone.0056190 · 3.23 Impact Factor
Show more