scholarly journals Astaxanthin extends lifespan via altered biogenesis of the mitochondrial respiratory chain complex III

2019 ◽  
Author(s):  
Ronit Hoffman ◽  
Laure D. Sultan ◽  
Ann Saada ◽  
Joseph Hirschberg ◽  
Oren Osterzetser-Biran ◽  
...  
Keyword(s):  
Model Organism ◽  
Chain Complex ◽  
Mitochondrial Respiratory Chain ◽  
Industrial Applications ◽  
Complex Iii ◽  
Life Extension ◽  
Mitochondrial Respiratory Chain Complex ◽  
C Elegans ◽  
Species Effect

AbstractAstaxanthin is a keto-carotenoid produced in some bacteria and algae, which has very important industrial applications (i.e., in cosmetics, coloring additive in aquaculture and as a dietary supplement for human). Here, we analyzed the molecular basis of Astaxanthin-mediated prolongevity in the model organism, Caenorhabditis elegans. The increased lifespan effects of Astaxanthin are restricted in C. elegans to the adult phase and are uninfluenced by various other carotenoids tested. Genetic analyses indicated that the Astaxanthin-mediated life-extension relies on mitochondria activity, via the Rieske iron-sulfur polypeptide-1 (ISP-1), but is not influenced by the functions of other known longevity-related gene-loci, including CLK-1, DAF-2, DAT-16, EAT-2, GAS-1 GLP-1 or MEV-1. Biochemical analyses of native respiratory complexes showed that Astaxanthin affects the biogenesis of holo-complex III (and likely supercomplex I+III, as well). Effects on holo-CIII assembly and activity were also indicated by in-vitro assays, with mitochondria isolated from worms, rodents, human and plants, which were treated with Astaxanthin. These data indicated a cross-species effect on the oxidative phosphorylation (OXPHOS) machinery by the carotenoid, and provide with further insights into the molecular mechanism of animals longevity extension by Astaxanthin.Significance StatementAstaxanthin is a widely consumed pigment by animals and human. In this study we find that Astaxanthin, but not other tested carotenoids, significantly extends the lifespan of animals by affecting respiratory complex III (CIII) biogenesis of the mitochondria, in plants, C. elegans, rodents and human. We further propose a model to try explaining this effect of astaxanthin on animals’ longevity.

Novel Mycotoxin fromAcremonium exuviarumIs a Powerful Inhibitor of the Mitochondrial Respiratory Chain Complex III

2009 ◽  
Vol 22 (3) ◽  
pp. 565-573 ◽  
Author(s):  
Alexey G. Kruglov ◽  
Maria A. Andersson ◽  
Raimo Mikkola ◽  
Merja Roivainen ◽  
Laszlo Kredics ◽  
...  
Keyword(s):  
Respiratory Chain ◽  
Chain Complex ◽  
Mitochondrial Respiratory Chain ◽  
Complex Iii ◽  
Respiratory Chain Complex ◽  
Mitochondrial Respiratory Chain Complex ◽  
Mitochondrial Respiratory

Primary defects in lipid handling and resistance to exercise in myotubes from obese donors with and without type 2 diabetes

2020 ◽  
Vol 45 (2) ◽  
pp. 169-179 ◽  
Author(s):  
Nils Gunnar Løvsletten ◽  
Arild C. Rustan ◽  
Claire Laurens ◽  
G. Hege Thoresen ◽  
Cedric Moro ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Chain Complex ◽  
Mitochondrial Respiratory Chain ◽  
Oxidative Capacity ◽  
Mitochondrial Respiratory Chain Complex ◽  
Electrical Pulse Stimulation ◽  
Palmitate Uptake ◽  
Reduced Rate

Several studies have shown that human primary myotubes retain the metabolic characteristic of their donors in vitro. We have demonstrated, along with other researchers, a reduced lipid turnover and fat oxidation rate in myotubes derived from obese donors with and without type 2 diabetes (T2D). Because exercise is known to increase fat oxidative capacity in skeletal muscle, we investigated if in vitro exercise could restore primary defects in lipid handling in myotubes of obese individuals with and without T2D compared with lean nondiabetic donors. Primary myotubes cultures were derived from biopsies of lean, obese, and T2D subjects. One single bout of long-duration exercise was mimicked in vitro by electrical pulse stimulation (EPS) for 24 h. Lipid handling was measured using radiolabeled palmitate, metabolic gene expression by real-time qPCR, and proteins by Western blot. We first showed that myotubes from obese and T2D donors had increased uptake and incomplete oxidation of palmitate. This was associated with reduced mitochondrial respiratory chain complex II, III, and IV protein expression in myotubes from obese and T2D subjects. EPS stimulated palmitate oxidation in lean donors, while myotubes from obese and T2D donors were refractory to this effect. Interestingly, EPS increased total palmitate uptake in myotubes from lean donors while myotubes from T2D donors had a reduced rate of palmitate uptake into complex lipids and triacylglycerols. Novelty Myotubes from obese and T2D donors are characterized by primary defects in palmitic acid handling. Both obese and T2D myotubes are partially refractory to the beneficial effect of exercise on lipid handling.

scholarly journals Dihydromyricetin Attenuates Dexamethasone-Induced Muscle Atrophy by Improving Mitochondrial Function via the PGC-1α Pathway

2018 ◽  
Vol 49 (2) ◽  
pp. 758-779 ◽  
Author(s):  
Yujie Huang ◽  
Ka Chen ◽  
Qingbo Ren ◽  
Long Yi ◽  
Jundong Zhu ◽  
...  
Keyword(s):  
Muscle Atrophy ◽  
Mitochondrial Function ◽  
Chain Complex ◽  
Mitochondrial Respiratory Chain ◽  
Mitochondrial Morphology ◽  
Cross Sectional ◽  
Mitochondrial Respiratory Chain Complex ◽  
Underlying Mechanisms ◽  
Complex Activities

Background/Aims: Skeletal muscle atrophy is an important health issue and can impose tremendous economic burdens on healthcare systems. Glucocorticoids (GCs) are well-known factors that result in muscle atrophy observed in numerous pathological conditions. Therefore, the development of effective and safe therapeutic strategies for GC-induced muscle atrophy has significant clinical implications. Some natural compounds have been shown to effectively prevent muscle atrophy under several wasting conditions. Dihydromyricetin (DM), the most abundant flavonoid in Ampelopsis grossedentata, has a broad range of health benefits, but its effects on muscle atrophy are unclear. The purpose of this study was to evaluate the effects and underlying mechanisms of DM on muscle atrophy induced by the synthetic GC dexamethasone (Dex). Methods: The effects of DM on Dex-induced muscle atrophy were assessed in Sprague-Dawley rats and L6 myotubes. Muscle mass and myofiber cross-sectional areas were analyzed in gastrocnemius muscles. Muscle function was evaluated by a grip strength test. Myosin heavy chain (MHC) content and myotube diameter were measured in myotubes. Mitochondrial morphology was observed by transmission electron microscopy and confocal laser scanning microscopy. Mitochondrial DNA (mtDNA) was quantified by real-time PCR. Mitochondrial respiratory chain complex activities were examined using the MitoProfile Rapid Microplate Assay Kit, and mitochondrial membrane potential was assessed by JC-1 staining. Protein levels of mitochondrial biogenesis and dynamics markers were detected by western blotting. Myotubes were transfected with siRNAs targeting peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), mitochondrial transcription factor A (TFAM) and mitofusin-2 (mfn2) to determine the underlying mechanisms. Results: In vivo, DM preserved muscles from weight and average fiber cross-sectional area losses and improved grip strength. In vitro, DM prevented the decrease in MHC content and myotube diameter. Moreover, DM stimulated mitochondrial biogenesis and promoted mitochondrial fusion, rescued the reduced mtDNA content, improved mitochondrial morphology, prevented the collapse in mitochondrial membrane potential and enhanced mitochondrial respiratory chain complex activities; these changes restored mitochondrial function and improved protein metabolism, contributing to the prevention of Dex-induced muscle atrophy. Furthermore, the protective effects of DM on mitochondrial function and muscle atrophy were alleviated by PGC-1α siRNA, TFAM siRNA and mfn2 siRNA transfection in vitro. Conclusion: DM attenuated Dex-induced muscle atrophy by reversing mitochondrial dysfunction, which was partially mediated by the PGC-1α/TFAM and PGC-1α/mfn2 signaling pathways. Our findings may open new avenues for identifying natural compounds that improve mitochondrial function as promising candidates for the management of muscle atrophy.

scholarly journals The Role of Dihydroorotate Dehydrogenase in Apoptosis Induction in Response to Inhibition of the Mitochondrial Respiratory Chain Complex III

Acta Naturae ◽  
2014 ◽  
Vol 6 (1) ◽  
pp. 69-75 ◽  
Author(s):  
A. A. Khutornenko ◽  
A. A. Dalina ◽  
B. V. Chernyak ◽  
P. M. Chumakov ◽  
A. G. Evstafieva
Keyword(s):  
Cell Death ◽  
Respiratory Chain ◽  
De Novo ◽  
Apoptotic Cell ◽  
Chain Complex ◽  
Mitochondrial Respiratory Chain ◽  
Pyrimidine Biosynthesis ◽  
Complex Iii ◽  
Mitochondrial Respiratory Chain Complex ◽  
Mitochondrial Respiratory

A mechanism for the induction of programmed cell death (apoptosis) upon dysfunction of the mitochondrial respiratory chain has been studied. Previously, we had found that inhibition of mitochondrial cytochrome bc1, a component of the electron transport chain complex III, leads to activation of tumor suppressor p53, followed by apoptosis induction. The mitochondrial respiratory chain is coupled to the de novo pyrimidine biosynthesis pathway via the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH). The p53 activation induced in response to the inhibition of the electron transport chain complex III has been shown to be triggered by the impairment of the de novo pyrimidine biosynthesis due to the suppression of DHODH. However, it remained unclear whether the suppression of the DHODH function is the main cause of the observed apoptotic cell death. Here, we show that apoptosis in human colon carcinoma cells induced by the mitochondrial respiratory chain complex III inhibition can be prevented by supplementation with uridine or orotate (products of the reaction catalyzed by DHODH) rather than with dihydroorotate (a DHODH substrate). We conclude that apoptosis is induced in response to the impairment of the de novo pyrimidine biosynthesis caused by the inhibition of DHODH. The conclusion is supported by the experiment showing that downregulation of DHODH by RNA interference leads to accumulation of the p53 tumor suppressor and to apoptotic cell death.

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