| 1. |
- Anisimov, Vladimir N., et al.
(författare)
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Effects of the mitochondria-targeted antioxidant SkQ1 on lifespan of rodents
- 2011
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Ingår i: Aging. - 1945-4589. ; 3:11, s. 1110-1119
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Tidskriftsartikel (refereegranskat)abstract
- The effect of the mitochondria-targeted, plastoquinone-containing antioxidant SkQ1 on the lifespan of outbred mice and of three strains of inbred mice was studied. To this end, low pathogen (LP) or specific pathogen free (SPF) vivaria in St. Petersburg, Moscow, and Stockholm were used. For comparison, we also studied mole-voles and dwarf hamsters, two wild species of small rodents kept under simulated natural conditions. It was found that substitution of a LP vivarium for a conventional (non-LP) one doubled the lifespan of female outbred mice, just as SkQ1 did in a non-LP vivarium. SkQ1 prevented age-dependent disappearance of estrous cycles of outbred mice in both LP and non-LP vivaria. In the SPF vivarium in Moscow, male BALB/c mice had shorter lifespan than females, and SkQ1 increased their lifespan to the values of the females. In the females, SkQ1 retarded development of such trait of aging as heart mass increase. Male C57Bl/6 mice housed individually in the SPF vivarium in Stockholm lived as long as females. SkQ1 increased the male lifespan, the longevity of the females being unchanged. SkQ1 did not change food intake by these mice. Dwarf hamsters and mole-voles kept in outdoor cages or under simulated natural conditions lived longer if treated with SkQ1. The effect of SkQ1 on longevity of females is assumed to mainly be due to retardation of the age-linked decline of the immune system. For males under LP or SPF conditions, SkQ1 increased the lifespan, affecting also some other system(s) responsible for aging.
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| 2. |
- Gao, Yun, et al.
(författare)
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Establishing the potency of N-acyl amino acids versus conventional fatty acids as thermogenic uncouplers in cells and mitochondria from different tissues
- 2022
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Ingår i: Biochimica et Biophysica Acta - Bioenergetics. - : Elsevier BV. - 0005-2728 .- 1879-2650. ; 1863:4
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Tidskriftsartikel (refereegranskat)abstract
- The possibility that N-acyl amino acids could function as brown or brite/beige adipose tissue-derived lipokines that could induce UCP1-independent thermogenesis by uncoupling mitochondrial respiration in several peripheral tissues is of significant physiological interest. To quantify the potency of N-acyl amino acids versus conventional fatty acids as thermogenic inducers, we have examined the affinity and efficacy of two pairs of such compounds: oleate versus N-oleoyl-leucine and arachidonate versus N-arachidonoyl-glycine in cells and mitochondria from different tissues. We found that in cultures of the muscle-derived L6 cell line, as well as in primary cultures of murine white, brite/beige and brown adipocytes, the N-acyl amino acids were proficient uncouplers but that they did not systematically display higher affinity or potency than the conventional fatty acids, and they were not as efficient uncouplers as classical protonophores (FCCP). Higher concentrations of the N-acyl amino acids (as well as of conventional fatty acids) were associated with signs of deleterious effects on the cells. In liver mitochondria, we found that the N-acyl amino acids uncoupled similarly to conventional fatty acids, thus apparently via activation of the adenine nucleotide transporter-2. In brown adipose tissue mitochondria, the N-acyl amino acids were able to activate UCP1, again similarly to conventional fatty acids. We thus conclude that the formation of the acyl-amino acid derivatives does not confer upon the corresponding fatty acids an enhanced ability to induce thermogenesis in peripheral tissues, and it is therefore unlikely that the N-acyl amino acids are of specific physiological relevance as UCP1-independent thermogenic compounds.
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| 3. |
- Manskikh, V. N., et al.
(författare)
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Age-associated murine cardiac lesions are attenuated by the mitochondria-targeted antioxidant SkQ1
- 2015
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Ingår i: Histology and Histopathology. - 0213-3911 .- 1699-5848. ; 30:3, s. 353-360
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Tidskriftsartikel (refereegranskat)abstract
- Age-related changes in mammalian hearts often result in cardiac hypertrophy and fibrosis that are preceded by inflammatory infiltration. In this paper, we show that lifelong treatment of BALB/c and C57BL/6 mice with the mitochondria-targeted antioxidant SkQ1 retards senescence-associated myocardial disease (cardiomyopathy), cardiac hypertrophy, and diffuse myocardial fibrosis. To investigate the molecular basis of the action of SkQ1, we have applied DNA microarray analysis. The global gene expression profile in heart tissues was not significantly affected by administration of SkQ1. However, we found some small but statistically significant modifications of the pathways related to cell-to-cell contact, adhesion, and leukocyte infiltration. Probably, SkQ1-induced decrease in leukocyte and mesenchymal cell adhesion and/or infiltration lead to a reduction in age-related inflammation and subsequent fibrosis. The data indicate a causative role of mitochondrial reactive oxygen species in cardiovascular aging and imply that SkQ1 has potential as a drug against age-related cardiac dysfunction.
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| 4. |
- Abreu-Vieira, Gustavo, et al.
(författare)
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Cidea improves the metabolic profile through expansion of adipose tissue
- 2015
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- In humans, Cidea (cell death-inducing DNA fragmentation factor alpha-like effector A) is highly but variably expressed in white fat, and expression correlates with metabolic health. Here we generate transgenic mice expressing human Cidea in adipose tissues (aP2-hCidea mice) and show that Cidea is mechanistically associated with a robust increase in adipose tissue expandability. Under humanized conditions (thermoneutrality, mature age and prolonged exposure to high-fat diet), aP2-hCidea mice develop a much more pronounced obesity than their wild-type littermates. Remarkably, the malfunctioning of visceral fat normally caused by massive obesity is fully overcome-perilipin 1 and Akt expression are preserved, tissue degradation is prevented, macrophage accumulation is decreased and adiponectin expression remains high. Importantly, the aP2-hCidea mice display enhanced insulin sensitivity. Our data establish a functional role for Cidea and suggest that, in humans, the association between Cidea levels in white fat and metabolic health is not only correlative but also causative.
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| 5. |
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| 6. |
- Bruton, Joseph D., et al.
(författare)
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Increased fatigue resistance linked to Ca(2+)-stimulated mitochondrial biogenesis in muscle fibres of cold-acclimated mice
- 2010
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Ingår i: Journal of Physiology. - : Wiley. - 0022-3751 .- 1469-7793. ; 588:21, s. 4275-4288
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Tidskriftsartikel (refereegranskat)abstract
- Mammals exposed to a cold environment initially generate heat by repetitive muscle activity (shivering). Shivering is successively replaced by the recruitment of uncoupling protein-1 (UCP1)-dependent heat production in brown adipose tissue. Interestingly, adaptations observed in skeletal muscles of cold-exposed animals are similar to those observed with endurance training. We hypothesized that increased myoplasmic free [Ca2+] ([Ca2+]i) is important for these adaptations. To test this hypothesis, experiments were performed on flexor digitorum brevis (FDB) muscles, which do not participate in the shivering response, of adult wild-type (WT) and UCP1-ablated (UCP1-KO) mice kept either at room temperature (24 ºC) or cold-acclimated (4 ºC) for 4-5 weeks. [Ca2+]i (measured with indo-1) and force were measured under control conditions and during fatigue induced by repeated tetanic stimulation in intact single fibres. The results show no differences between fibres from WT and UCP1-KO mice. However, muscle fibres from cold-acclimated mice showed significant increases in basal [Ca2+]i (~50%), tetanic [Ca2+]i (~40%), and sarcoplasmic reticulum (SR) Ca2+ leak (~four-fold) as compared to fibres from room-temperature mice. Muscles of cold-acclimated mice showed increased expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and increased citrate synthase activity (reflecting increased mitochondrial content). Fibres of cold-acclimated mice were more fatigue resistant with higher tetanic [Ca2+]i and less force loss during fatiguing stimulation. In conclusion, cold exposure induces changes in FDB muscles similar to those observed with endurance training and we propose that increased [Ca2+]i is a key factor underlying these adaptations.
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| 7. |
- Fischer, Alexander W., et al.
(författare)
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UCP1 inhibition in Cidea-overexpressing mice is physiologically counteracted by brown adipose tissue hyperrecruitment
- 2017
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Ingår i: American Journal of Physiology. Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 312:1, s. e72-E87
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Tidskriftsartikel (refereegranskat)abstract
- Cidea is a gene highly expressed in thermogenesis- competent (UCP1-containing) adipose cells, both brown and brite/beige. Here, we initially demonstrate a remarkable adipose-depot specific regulation of Cidea expression. In classical brown fat, Cidea mRNA is expressed continuously and invariably, irrespective of tissue recruitment. However, Cidea protein levels are regulated posttranscriptionally, being conspicuously induced in the thermogenically recruited state. In contrast, in brite fat, Cidea protein levels are regulated at the transcriptional level, and Cidea mRNA and protein levels are proportional to tissue briteness. Although routinely followed as a thermogenic molecular marker, Cidea function is not clarified. Here, we employed a gain-of-function approach to examine a possible role of Cidea in the regulation of thermogenesis. We utilized transgenic aP2-hCidea mice that overexpress human Cidea in all adipose tissues. We demonstrate that UCP1 activity is markedly suppressed in brown-fat mitochondria isolated from aP2-hCidea mice. However, mitochondrial UCP1 protein levels were identical in wildtype and transgenic mice. This implies a regulatory effect of Cidea on UCP1 activity, but as we demonstrate that Cidea itself is not localized to mitochondria, we propose an indirect inhibitory effect. The Cidea-induced inhibition of UCP1 activity (observed in isolated mitochondria) is physiologically relevant since the mice, through an appropriate homeostatic compensatory mechanism, increased the total amount of UCP1 in the tissue to exactly match the diminished thermogenic capacity of the UCP1 protein and retain unaltered nonshivering thermogenic capacity. Thus, we verified Cidea as being a marker of thermogenesis-competent adipose tissues, but we conclude that Cidea, unexpectedly, functions molecularly as an indirect inhibitor of thermogenesis.
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| 8. |
- Gizatullina, Zemfira Z., et al.
(författare)
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Effect of transforming growth factor-beta on calcium homeostasis inprostate carcinoma cells.
- 2003
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Ingår i: Biochem Biophys Res Commun. ; 304, s. 643-
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Tidskriftsartikel (refereegranskat)abstract
- Ca(2+) plays a fundamental role in the control of a variety of cellular functions, in particular, in energy metabolism and apoptosis. In this study, we show that TGF-beta at concentrations of 0.1-1.0 ng/ml transiently increases the level of intracellular Ca(2+) ([Ca(2+)](in)) in human prostate carcinoma, PC-3U, cells. Experiments with mitochondrial inhibitors (oligomycin and antimycin A) and an inhibitor of endoplasmic reticulum Ca(2+) uptake (BHQ) implied that the effect of TGF-beta1 was due to an effect on the mitochondria. TGF-beta1 treatment resulted in a decrease in ATP synthesis and to a depolarisation, leading to a release of Ca(2+) from mitochondria and decreased activity of the Ca(2+) pumps. Analysis of the mitochondria within the PC-3U cells by polarography and membrane potential-sensitive dye (Rhodamine 123) confirmed that under these experimental conditions, TGF-beta1 inhibited ATP synthesis and depolarised the mitochondria. The results implicate that TGF-beta1 affects the function of the mitochondria and may be of significance for the understanding of the proapoptotic effect of TGF-beta1 in these cells.
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| 9. |
- Gómez Rodríguez, Alexia, et al.
(författare)
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Elovl2-Ablation Leads to Mitochondrial Membrane Fatty Acid Remodeling and Reduced Efficiency in Mouse Liver Mitochondria
- 2022
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Ingår i: Nutrients. - : MDPI AG. - 2072-6643. ; 14:3
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Tidskriftsartikel (refereegranskat)abstract
- The fatty acid elongase elongation of very long-chain fatty acids protein 2 (ELOVL2) controls the elongation of polyunsaturated fatty acids (PUFA) producing precursors for omega-3, docosahexaenoic acid (DHA), and omega-6, docosapentaenoic acid (DPAn-6) in vivo. Expectedly, Elovl2-ablation drastically reduced the DHA and DPAn-6 in liver mitochondrial membranes. Unexpectedly, however, total PUFAs levels decreased further than could be explained by Elovl2 ablation. The lipid peroxidation process was not involved in PUFAs reduction since malondialdehyde-lysine (MDAL) and other oxidative stress biomarkers were not enhanced. The content of mitochondrial respiratory chain proteins remained unchanged. Still, membrane remodeling was associated with the high voltage-dependent anion channel (VDAC) and adenine nucleotide translocase 2 (ANT2), a possible reflection of the increased demand on phospholipid transport to the mitochondria. Mitochondrial function was impaired despite preserved content of the respiratory chain proteins and the absence of oxidative damage. Oligomycin-insensitive oxygen consumption increased, and coefficients of respiratory control were reduced by 50%. The mitochondria became very sensitive to fatty acid-induced uncoupling and permeabilization, where ANT2 is involved. Mitochondrial volume and number of peroxisomes increased as revealed by transmission electron microscopy. In conclusion, the results imply that endogenous DHA production is vital for the normal function of mouse liver mitochondria and could be relevant not only for mice but also for human metabolism.
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| 10. |
- Hagberg, C. E., et al.
(författare)
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Flow Cytometry of Mouse and Human Adipocytes for the Analysis of Browning and Cellular Heterogeneity
- 2018
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 24:10
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Tidskriftsartikel (refereegranskat)abstract
- Adipocytes, once considered simple lipid-storing cells, are rapidly emerging as complex cells with many biologically diverse functions. A powerful high-throughput method for analyzing single cells is flow cytometry. Several groups have attempted to analyze and sort freshly isolated adipocytes; however, using an adipocyte-specific reporter mouse, we demonstrate that these studies fail to detect the majority of white adipocytes. We define critical settings required for adipocyte flow cytometry and provide a rigid strategy for analyzing and sorting white and brown adipocyte populations. The applicability of our protocol is shown by sorting mouse adipocytes based on size or UCP1 expression and demonstrating that a subset of human adipocytes lacks the beta(2)-adrenergic receptor, particularly in the insulin-resistant state. In conclusion, the present study confers key technological insights for analyzing and sorting mature adipocytes, opening up numerous downstream research applications.
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