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Shabalina, I., Edgar, D., Gibanova, N., Kalinovich, A., Petrovic, N., Vyssokikh, M. Y., . . . Nedergaard, J. (2024). Enhanced ROS Production in Mitochondria from Prematurely Aging mtDNA Mutator Mice. Biochemistry (Moscow), 89(2), 279-298
Åpne denne publikasjonen i ny fane eller vindu >>Enhanced ROS Production in Mitochondria from Prematurely Aging mtDNA Mutator Mice
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2024 (engelsk)Inngår i: Biochemistry (Moscow), ISSN 0006-2979, E-ISSN 1608-3040, Vol. 89, nr 2, s. 279-298Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

An increase in mitochondrial DNA (mtDNA) mutations and an ensuing increase in mitochondrial reactive oxygen species (ROS) production have been suggested to be a cause of the aging process (the mitochondrial hypothesis of aging). In agreement with this, mtDNA-mutator mice accumulate a large amount of mtDNA mutations, giving rise to defective mitochondria and an accelerated aging phenotype. However, incongruously, the rates of ROS production in mtDNA mutator mitochondria have generally earlier been reported to be lower - not higher - than in wildtype, thus apparently invalidating the mitochondrial hypothesis of aging. We have here re-examined ROS production rates in mtDNA-mutator mice mitochondria. Using traditional conditions for measuring ROS (succinate in the absence of rotenone), we indeed found lower ROS in the mtDNA-mutator mitochondria compared to wildtype. This ROS mainly results from reverse electron flow driven by the membrane potential, but the membrane potential reached in the isolated mtDNA-mutator mitochondria was 33 mV lower than that in wildtype mitochondria, due to the feedback inhibition of succinate oxidation by oxaloacetate, and to a lower oxidative capacity in the mtDNA-mutator mice, explaining the lower ROS production. In contrast, in normal forward electron flow systems (pyruvate (or glutamate) + malate or palmitoyl-CoA + carnitine), mitochondrial ROS production was higher in the mtDNA-mutator mitochondria. Particularly, even during active oxidative phosphorylation (as would be ongoing physiologically), higher ROS rates were seen in the mtDNA-mutator mitochondria than in wildtype. Thus, when examined under physiological conditions, mitochondrial ROS production rates are indeed increased in mtDNA-mutator mitochondria. While this does not prove the validity of the mitochondrial hypothesis of aging, it may no longer be said to be negated in this respect. This paper is dedicated to the memory of Professor Vladimir P. Skulachev.

Emneord
mtDNA mutator mice, ROS production, aging, succinate, membrane potential, oxidative phosphorylation
HSV kategori
Identifikatorer
urn:nbn:se:su:diva-228605 (URN)10.1134/S0006297924020081 (DOI)001190797800013 ()38622096 (PubMedID)2-s2.0-85188236462 (Scopus ID)
Tilgjengelig fra: 2024-04-23 Laget: 2024-04-23 Sist oppdatert: 2024-04-23bibliografisk kontrollert
Gómez Rodríguez, A., Talamonti, E., Naudi, A., Kalinovich, A. V., Pauter, A. M., Barja, G., . . . Shabalina, I. G. (2022). Elovl2-Ablation Leads to Mitochondrial Membrane Fatty Acid Remodeling and Reduced Efficiency in Mouse Liver Mitochondria. Nutrients, 14(3), Article ID 559.
Åpne denne publikasjonen i ny fane eller vindu >>Elovl2-Ablation Leads to Mitochondrial Membrane Fatty Acid Remodeling and Reduced Efficiency in Mouse Liver Mitochondria
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2022 (engelsk)Inngår i: Nutrients, E-ISSN 2072-6643, Vol. 14, nr 3, artikkel-id 559Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

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.

Emneord
docosahexaenoic acid (DHA) deficiency, mitochondrial function, polyunsaturated fatty acids, membrane permeabilization, oxidative damage markers, adenine nucleotide translocase
HSV kategori
Identifikatorer
urn:nbn:se:su:diva-202398 (URN)10.3390/nu14030559 (DOI)000754768000001 ()
Tilgjengelig fra: 2022-02-24 Laget: 2022-02-24 Sist oppdatert: 2023-08-28bibliografisk kontrollert
Gao, Y., Shabalina, I. G., Braz, G. R., Cannon, B., Yang, G. & Nedergaard, J. (2022). Establishing the potency of N-acyl amino acids versus conventional fatty acids as thermogenic uncouplers in cells and mitochondria from different tissues. Biochimica et Biophysica Acta - Bioenergetics, 1863(4), Article ID 148542.
Åpne denne publikasjonen i ny fane eller vindu >>Establishing the potency of N-acyl amino acids versus conventional fatty acids as thermogenic uncouplers in cells and mitochondria from different tissues
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2022 (engelsk)Inngår i: Biochimica et Biophysica Acta - Bioenergetics, ISSN 0005-2728, E-ISSN 1879-2650, Vol. 1863, nr 4, artikkel-id 148542Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

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.

Emneord
Adenine nucleotide transporter, Fatty acids, N-acyl amino acids, Nonshivering thermogenesis, Uncoupling protein-1, N-oleoyl-leu, N-arachidonoyl-gly
HSV kategori
Identifikatorer
urn:nbn:se:su:diva-204413 (URN)10.1016/j.bbabio.2022.148542 (DOI)000781771000002 ()35192808 (PubMedID)
Tilgjengelig fra: 2022-05-04 Laget: 2022-05-04 Sist oppdatert: 2022-05-04bibliografisk kontrollert
Bokhari, M. H., Halleskog, C., Åslund, A., Boulet, N., Casadesús Rendos, E., de Jong, J. M., . . . Bengtsson, T. (2021). Isothermal microcalorimetry measures UCP1-mediated thermogenesis in mature brite adipocytes. Communications Biology, 4(1), Article ID 1108.
Åpne denne publikasjonen i ny fane eller vindu >>Isothermal microcalorimetry measures UCP1-mediated thermogenesis in mature brite adipocytes
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2021 (engelsk)Inngår i: Communications Biology, E-ISSN 2399-3642, Vol. 4, nr 1, artikkel-id 1108Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

The activation of thermogenesis in adipose tissue has emerged as an important target for the development of novel anti-obesity therapies. Using multi-well isothermal microcalorimetry, we have demonstrated that mature murine brown and brite adipocytes produce quantifiable heat upon β3-AR stimulation, independently of any anaerobic mechanisms. Additionally, in brite adipocytes lacking UCP1 protein, β3-AR stimulation still induces heat production, albeit to a much lower extent than in their wildtype counterparts, suggesting that UCP1 is an essential component of adrenergic induced thermogenesis in murine brite adipocytes exvivo. Similarly, we could observe an increase in heat production in human-derived adipocytes (hMADS) upon β-AR stimulation. Collectively, these results establish the use of isothermal microcalorimetry as a sensitive and accurate technique for measuring thermogenic responses in intact mature brite adipocytes from murine and human origin.

HSV kategori
Identifikatorer
urn:nbn:se:su:diva-198698 (URN)10.1038/s42003-021-02639-4 (DOI)000697665400003 ()34548622 (PubMedID)
Tilgjengelig fra: 2021-11-15 Laget: 2021-11-15 Sist oppdatert: 2022-02-28bibliografisk kontrollert
Luijten, I. H. N., Brooks, K., Boulet, N., Shabalina, I. G., Jaiprakash, A., Carlsson, B., . . . Nedergaard, J. (2019). Glucocorticoid-Induced Obesity Develops Independently of UCP1. Cell Reports, 27(6), 1686-1698
Åpne denne publikasjonen i ny fane eller vindu >>Glucocorticoid-Induced Obesity Develops Independently of UCP1
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2019 (engelsk)Inngår i: Cell Reports, E-ISSN 2211-1247, Vol. 27, nr 6, s. 1686-1698Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

An excess of glucocorticoids leads to the development of obesity in both mice and humans, but the mechanism for this is unknown. Here, we determine the extent to which decreased BAT thermogenic capacity (as a result of glucocorticoid treatment) contributes to the development of obesity. Contrary to previous suggestions, we show that only in mice housed at thermoneutrality (30 degrees C) does corticosterone treatment reduce total BAT UCP1 protein. This reduction is reflected in reduced brown adipocyte cellular and mitochondrial UCP1-dependent respiration. However, glucocorticoid-induced obesity develops to the same extent in animals housed at 21 degrees C and 30 degrees C, whereas total BAT UCP1 protein levels differ 100-fold between the two groups. In corticosterone-treated wild-type and UCP1 knockout mice housed at 30 degrees C, obesity also develops to the same extent. Thus, our results demonstrate that the development of glucocorticoid-induced obesity is not caused by a decreased UCP1-dependent thermogenic capacity.

HSV kategori
Identifikatorer
urn:nbn:se:su:diva-169257 (URN)10.1016/j.celrep.2019.04.041 (DOI)000467058500006 ()31067456 (PubMedID)
Tilgjengelig fra: 2019-06-12 Laget: 2019-06-12 Sist oppdatert: 2024-01-17bibliografisk kontrollert
Hagberg, C. E., Li, Q., Kutschke, M., Bhowmick, D., Kiss, E., Shabalina, I. G., . . . Spalding, K. L. (2018). Flow Cytometry of Mouse and Human Adipocytes for the Analysis of Browning and Cellular Heterogeneity. Cell Reports, 24(10), 2746-2756
Åpne denne publikasjonen i ny fane eller vindu >>Flow Cytometry of Mouse and Human Adipocytes for the Analysis of Browning and Cellular Heterogeneity
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2018 (engelsk)Inngår i: Cell Reports, E-ISSN 2211-1247, Vol. 24, nr 10, s. 2746-2756Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

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.

Emneord
adipocyte, adipose tissue, flow cytometry, FACS, mouse, human, uncoupled protein 1, beta 2 adrenergic receptor
HSV kategori
Identifikatorer
urn:nbn:se:su:diva-160206 (URN)10.1016/j.celrep.2018.08.006 (DOI)000443588800021 ()30184507 (PubMedID)
Tilgjengelig fra: 2018-09-26 Laget: 2018-09-26 Sist oppdatert: 2024-01-17bibliografisk kontrollert
Schilperoort, M., van Dam, A. D., Hoeke, G., Shabalina, I. G., Okolo, A., Hanyaloglu, A. C., . . . Christian, M. (2018). The GPR120 agonist TUG-891 promotes metabolic health by stimulating mitochondrial respiration in brown fat. EMBO Molecular Medicine, 10(3), Article ID e8047.
Åpne denne publikasjonen i ny fane eller vindu >>The GPR120 agonist TUG-891 promotes metabolic health by stimulating mitochondrial respiration in brown fat
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2018 (engelsk)Inngår i: EMBO Molecular Medicine, ISSN 1757-4676, E-ISSN 1757-4684, Vol. 10, nr 3, artikkel-id e8047Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Brown adipose tissue (BAT) activation stimulates energy expenditure in human adults, which makes it an attractive target to combat obesity and related disorders. Recent studies demonstrated a role for G protein-coupled receptor 120 (GPR120) in BAT thermogenesis. Here, we investigated the therapeutic potential of GPR120 agonism and addressed GPR120-mediated signaling in BAT. We found that activation of GPR120 by the selective agonist TUG-891 acutely increases fat oxidation and reduces body weight and fat mass in C57Bl/6J mice. These effects coincided with decreased brown adipocyte lipid content and increased nutrient uptake by BAT, confirming increased BAT activity. Consistent with these observations, GPR120 deficiency reduced expression of genes involved in nutrient handling in BAT. Stimulation of brown adipocytes invitro with TUG-891 acutely induced O-2 consumption, through GPR120-dependent and GPR120-independent mechanisms. TUG-891 not only stimulated GPR120 signaling resulting in intracellular calcium release, mitochondrial depolarization, and mitochondrial fission, but also activated UCP1. Collectively, these data suggest that activation of brown adipocytes with the GPR120 agonist TUG-891 is a promising strategy to increase lipid combustion and reduce obesity.

Emneord
brown adipose tissue, Ca2+, GPR120, lipid metabolism, mitochondria
HSV kategori
Identifikatorer
urn:nbn:se:su:diva-154807 (URN)10.15252/emmm.201708047 (DOI)000426769000003 ()29343498 (PubMedID)
Tilgjengelig fra: 2018-04-13 Laget: 2018-04-13 Sist oppdatert: 2022-03-23bibliografisk kontrollert
Shabalina, I. G., Vyssokikh, M. Y., Gibanova, N., Csikasz, R. I., Edgar, D., Hallden-Waldemarson, A., . . . Nedergaard, J. (2017). Improved health-span and lifespan in mtDNA mutator mice treated with the mitochondrially targeted antioxidant SkQ1. Aging, 9(2), 315-339
Åpne denne publikasjonen i ny fane eller vindu >>Improved health-span and lifespan in mtDNA mutator mice treated with the mitochondrially targeted antioxidant SkQ1
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2017 (engelsk)Inngår i: Aging, ISSN 1945-4589, E-ISSN 1945-4589, Vol. 9, nr 2, s. 315-339Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

MtDNA mutator mice exhibit marked features of premature aging. We find that these mice treated from age of approximate to 100 days with the mitochondria-targeted antioxidant SkQ1 showed a delayed appearance of traits of aging such as kyphosis, alopecia, lowering of body temperature, body weight loss, as well as ameliorated heart, kidney and liver pathologies. These effects of SkQ1 are suggested to be related to an alleviation of the effects of an enhanced reactive oxygen species (ROS) level in mtDNA mutator mice: the increased mitochondrial ROS released due to mitochondrial mutations probably interact with polyunsaturated fatty acids in cardiolipin, releasing malondialdehyde and 4-hydroxynonenal that form protein adducts and thus diminishes mitochondrial functions. SkQ1 counteracts this as it scavenges mitochondrial ROS. As the results, the normal mitochondrial ultrastructure is preserved in liver and heart; the phosphorylation capacity of skeletal muscle mitochondria as well as the thermogenic capacity of brown adipose tissue is also improved. The SkQ1-treated mice live significantly longer (335 versus 290 days). These data may be relevant in relation to treatment of mitochondrial diseases particularly and the process of aging in general.

Emneord
reactive oxygen species, oxidative stress, mitochondria, cardiolipin, thermogenesis, brown adipose tissue, longevity
HSV kategori
Identifikatorer
urn:nbn:se:su:diva-142559 (URN)10.18632/aging.101174 (DOI)000396892500005 ()28209927 (PubMedID)
Tilgjengelig fra: 2017-05-03 Laget: 2017-05-03 Sist oppdatert: 2022-03-23bibliografisk kontrollert
Fischer, A. W., Shabalina, I. G., Mattsson, C. L., Abreu-Vieira, G., Cannon, B., Nedergaard, J. & Petrovic, N. (2017). UCP1 inhibition in Cidea-overexpressing mice is physiologically counteracted by brown adipose tissue hyperrecruitment. American Journal of Physiology. Endocrinology and Metabolism, 312(1), e72-E87
Åpne denne publikasjonen i ny fane eller vindu >>UCP1 inhibition in Cidea-overexpressing mice is physiologically counteracted by brown adipose tissue hyperrecruitment
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2017 (engelsk)Inngår i: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 312, nr 1, s. e72-E87Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

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.

Emneord
cell death-inducing DNA fragmentation factor alpha-like effector A, uncoupling protein 1, nonshivering thermogenesis, brown adipose tissue, brite adipose tissue, beige adipose tissue
HSV kategori
Identifikatorer
urn:nbn:se:su:diva-141290 (URN)10.1152/ajpendo.00284.2016 (DOI)000393898700008 ()27923808 (PubMedID)
Tilgjengelig fra: 2017-04-04 Laget: 2017-04-04 Sist oppdatert: 2022-02-28bibliografisk kontrollert
Shabalina, I. G., Kalinovich, A. V., Cannon, B. & Nedergaard, J. (2016). Metabolically inert perfluorinated fatty acids directly activate uncoupling protein 1 in brown-fat mitochondria. Archives of Toxicology, 90(5), 1117-1128
Åpne denne publikasjonen i ny fane eller vindu >>Metabolically inert perfluorinated fatty acids directly activate uncoupling protein 1 in brown-fat mitochondria
2016 (engelsk)Inngår i: Archives of Toxicology, ISSN 0340-5761, E-ISSN 1432-0738, Vol. 90, nr 5, s. 1117-1128Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

The metabolically inert perfluorinated fatty acids perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) can display fatty acid-like activity in biological systems. The uncoupling protein 1 (UCP1) in brown adipose tissue is physiologically (re)activated by fatty acids, including octanoate. This leads to bioenergetically uncoupled energy dissipation (heat production, thermogenesis). We have examined here the possibility that PFOA/PFOS can directly (re)activate UCP1 in isolated mouse brown-fat mitochondria. In wild-type brown-fat mitochondria, PFOS and PFOA overcame GDP-inhibited thermogenesis, leading to increased oxygen consumption and dissipated membrane potential. The absence of this effect in brown-fat mitochondria from UCP1-ablated mice indicated that it occurred through activation of UCP1. A competitive type of inhibition by increased GDP concentrations indicated interaction with the same mechanistic site as that utilized by fatty acids. No effect was observed in heart mitochondria, i.e., in mitochondria without UCP1. The stimulatory effect of PFOA/PFOS was not secondary to non-specific mitochondrial membrane permeabilization or to ROS production. Thus, metabolic effects of perfluorinated fatty acids could include direct brown adipose tissue (UCP1) activation. The possibility that this may lead to unwarranted extra heat production and thus extra utilization of food resources, leading to decreased fitness in mammalian wildlife, is discussed, as well as possible negative effects in humans. However, a possibility to utilize PFOA-/PFOS-like substances for activating UCP1 therapeutically in obesity-prone humans may also be envisaged.

Emneord
Uncoupling protein 1, Brown adipose tissue mitochondria, Environmental pollution, Reactive oxygen species, Membrane potential, Mitochondrial permeabilization
HSV kategori
Identifikatorer
urn:nbn:se:su:diva-131537 (URN)10.1007/s00204-015-1535-4 (DOI)000374303400008 ()26041126 (PubMedID)
Tilgjengelig fra: 2016-07-01 Laget: 2016-06-21 Sist oppdatert: 2022-03-23bibliografisk kontrollert
Organisasjoner
Identifikatorer
ORCID-id: ORCID iD iconorcid.org/0000-0002-2915-6450