Insulin induces bioenergetic changes and alters mitochondrial dynamics in podocytes

in Journal of Endocrinology
Authors:
Irena Audzeyenka Laboratory of Molecular and Cellular Nephrology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Gdansk, Poland
Department of Molecular Biotechnology, Faculty of Chemistry, University of Gdansk, Gdansk, Poland

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https://orcid.org/0000-0002-1322-4332
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Patrycja Rachubik Laboratory of Molecular and Cellular Nephrology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Gdansk, Poland

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Dorota Rogacka Laboratory of Molecular and Cellular Nephrology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Gdansk, Poland
Department of Molecular Biotechnology, Faculty of Chemistry, University of Gdansk, Gdansk, Poland

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Moin A Saleem Bristol Renal, University of Bristol, Dorothy Hodgkin Building, Bristol, United Kingdom

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Agnieszka Piwkowska Laboratory of Molecular and Cellular Nephrology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Gdansk, Poland
Department of Molecular Biotechnology, Faculty of Chemistry, University of Gdansk, Gdansk, Poland

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Correspondence should be addressed to I Audzeyenka: iaudzeyenka@imdik.pan.pl
DOI:
https://doi.org/10.1530/JOE-23-0357
Volume/Issue:
Volume 261: Issue 3
Article Type:
Research Article
Article ID:
e230357
Online Publication Date:
17 Apr 2024
Copyright:
© the author(s) 2024
Restricted access
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Diabetic nephropathy (DN) is one of the most frequent complications of diabetes. Early stages of DN are associated with hyperinsulinemia and progressive insulin resistance in insulin-sensitive cells, including podocytes. The diabetic environment induces pathological changes, especially in podocyte bioenergetics, which is tightly linked with mitochondrial dynamics. The regulatory role of insulin in mitochondrial morphology in podocytes has not been fully elucidated. Therefore, the main goal of the present study was to investigate effects of insulin on the regulation of mitochondrial dynamics and bioenergetics in human podocytes. Biochemical analyses were performed to assess oxidative phosphorylation efficiency by measuring the oxygen consumption rate (OCR) and glycolysis by measuring the extracellular acidification rate (ECAR). mRNA and protein expression were determined by real-time polymerase chain reaction and Western blot. The intracellular mitochondrial network was visualized by MitoTracker staining. All calculations were conducted using CellProfiler software. Short-term insulin exposure exerted inhibitory effects on various parameters of oxidative respiration and adenosine triphosphate production, and glycolysis flux was elevated. After a longer time of treating cells with insulin, an increase in mitochondrial size was observed, accompanied by a reduction of expression of the mitochondrial fission markers DRP1 and FIS1 and an increase in mitophagy. Overall, we identified a previously unknown role for insulin in the regulation of oxidative respiration and glycolysis and elucidated mitochondrial dynamics in human podocytes. The present results emphasize the importance of the duration of insulin stimulation for its metabolic and molecular effects, which should be considered in clinical and experimental studies of DN.

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Print ISSN:
0022-0795
Online ISSN:
1479-6805
Copyright:
© the author(s) 2024
Article ID:
e230357
Article Type:
Research Article
Received Date:
16 Nov 2023
Accepted Date:
28 Mar 2024
Print Publication Date:
01 Jun 2024
Online Publication Date:
17 Apr 2024
Keywords:
insulin; mitochondria; bioenergetics; podocytes; diabetic nephropathy

  • Audzeyenka I, Bierżyńska A & & Lay AC 2022a Podocyte bioenergetics in the development of diabetic nephropathy: the role of mitochondria. Endocrinology 163 bqab234. (https://doi.org/10.1210/endocr/bqab234)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Audzeyenka I, Rachubik P, Typiak M, Kulesza T, Kalkowska D, Rogacka D, Rychłowski M, Angielski S, Saleem M & & Piwkowska A 2022b PTEN-induced kinase 1 deficiency alters albumin permeability and insulin signaling in podocytes. Journal of Molecular Medicine 100 903–915. (https://doi.org/10.1007/s00109-022-02204-4)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Audzeyenka I, Rachubik P, Typiak M, Kulesza T, Topolewska A, Rogacka D, Angielski S, Saleem MA & & Piwkowska A 2021 Hyperglycemia alters mitochondrial respiration efficiency and mitophagy in human podocytes. Experimental Cell Research 407 112758. (https://doi.org/10.1016/j.yexcr.2021.112758)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Audzeyenka I, Rogacka D, Piwkowska A, Rychlowski M, Bierla JB, Czarnowska E, Angielski S & & Jankowski M 2016 Reactive oxygen species are involved in insulin-dependent regulation of autophagy in primary rat podocytes. International Journal of Biochemistry and Cell Biology 75 23–33. (https://doi.org/10.1016/j.biocel.2016.03.015)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Barutta F, Bellini S & & Gruden G 2022 Mechanisms of podocyte injury and implications for diabetic nephropathy. Clinical Science 136 493–520. (https://doi.org/10.1042/CS20210625)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Crescenzo R, Bianco F, Mazzoli A, Giacco A, Liverini G & & Iossa S 2014 Mitochondrial efficiency and insulin resistance. Frontiers in Physiology 5 512. (https://doi.org/10.3389/fphys.2014.00512)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • del Campo A, Parra V, Vásquez-Trincado C, Gutiérrez T, Morales PE, López-Crisosto C, Bravo-Sagua R, Navarro-Marquez MF, Verdejo HE, Contreras-Ferrat A, et al.2014 Mitochondrial fragmentation impairs insulin-dependent glucose uptake by modulating Akt activity through mitochondrial Ca2+ uptake. American Journal of Physiology. Endocrinology and Metabolism 306 E1–E13. (https://doi.org/10.1152/ajpendo.00146.2013)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Ding W, Yang X, Lai K, Jiang Y & & Liu Y 2024 The potential of therapeutic strategies targeting mitochondrial biogenesis for the trea tment of insulin resistance and type 2 diabetes mellitus. Archives of Pharmacal Research 47 219–248. (https://doi.org/10.1007/s12272-024-01490-5)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Erecińska M, Deas J & & Silver IA 1995 The effect of pH on glycolysis and phosphofructokinase activity in cultured cells and synaptosomes. Journal of Neurochemistry 65 2765–2772. (https://doi.org/10.1046/j.1471-4159.1995.65062765.x)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Finocchietto P, Perez H, Blanco G, Miksztowicz V, Marotte C, Morales C, Peralta J, Berg G, Poderoso C, Poderoso JJ, et al.2022 Inhibition of mitochondrial fission by Drp-1 blockade by short-term leptin and Mdivi-1 treatment improves white adipose tissue abnormalities in obesity and diabetes. Pharmacological Research 178 106028. (https://doi.org/10.1016/j.phrs.2021.106028)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Galizzi G & & Di Carlo M 2022 Insulin and its key role for mitochondrial function/dysfunction and quality control: a shared link between dysmetabolism and neurodegeneration. Biology 11 943. (https://doi.org/10.3390/biology11060943)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Giacco F & & Brownlee M 2010 Oxidative stress and diabetic complications. Circulation Research 107 1058–1070. (https://doi.org/10.1161/CIRCRESAHA.110.223545)

  • Gucer S, Talim B, Asan E, Korkusuz P, Ozen S, Unal S, Kalkanoglu SH, Kale G & & Caglar M 2005 Focal segmental glomerulosclerosis associated with mitochondrial cytopathy: report of two cases with special emphasis on podocytes. Pediatric and Developmental Pathology 8 710–717. (https://doi.org/10.1007/s10024-005-0058-z)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hall AM & & Schuh CD 2016 Mitochondria as therapeutic targets in acute kidney injury. Current Opinion in Nephrology and Hypertension 25 355–362. (https://doi.org/10.1097/MNH.0000000000000228)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Haroon S & & Vermulst M 2016 Linking mitochondrial dynamics to mitochondrial protein quality control. Current Opinion in Genetics and Development 38 68–74. (https://doi.org/10.1016/j.gde.2016.04.004)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hou Y, Li S, Wu M, Wei J, Ren Y, Du C, Wu H, Han C, Duan H & & Shi Y 2016 Mitochondria-targeted peptide SS-31 attenuates renal injury via an antioxidant effect in diabetic nephropathy. American Journal of Physiology. Renal Physiology 310 F547–F559. (https://doi.org/10.1152/ajprenal.00574.2014)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Jaldin-Fincati JR, Pereira RVS, Bilan PJ & & Klip A 2018 Insulin uptake and action in microvascular endothelial cells of lymphatic and blood origin. American Journal of Physiology. Endocrinology and Metabolism 315 E204–E217. (https://doi.org/10.1152/ajpendo.00008.2018)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Jheng HF, Tsai PJ, Guo SM, Kuo LH, Chang CS, Su IJ, Chang CR & & Tsai YS 2012 Mitochondrial fission contributes to mitochondrial dysfunction and insulin resistance in skeletal muscle. Molecular and Cellular Biology 32 309–319. (https://doi.org/10.1128/MCB.05603-11)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kabra UD & & Jastroch M 2023 Mitochondrial dynamics and insulin secretion. International Journal of Molecular Sciences 24 13782. (https://doi.org/10.3390/ijms241813782)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Karwi QG, Wagg CS, Altamimi TR, Uddin GM, Ho KL, Darwesh AM, Seubert JM & & Lopaschuk GD 2020 Insulin directly stimulates mitochondrial glucose oxidation in the heart. Cardiovascular Diabetology 19 207. (https://doi.org/10.1186/s12933-020-01177-3)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Klip A, Ramlal T & & Cragoe EJ Jr 1986 Insulin-induced cytoplasmic alkalinization and glucose transport in muscle cells. American Journal of Physiology 250 C720–C728. (https://doi.org/10.1152/ajpcell.1986.250.5.C720)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lowell BB & & Shulman GI 2005 Mitochondrial dysfunction and type 2 diabetes. Science 307 384–387. (https://doi.org/10.1126/science.1104343)

  • Ma F, Li H, Huo H, Han Q, Liao J, Zhang H, Li Y, Pan J, Hu L, Guo J, et al.2023 N-acetyl-L-cysteine alleviates FUNDC1-mediated mitophagy by regulating mitochondrial dynamics in type 1 diabetic nephropathy canine. Life Sciences 313 121278. (https://doi.org/10.1016/j.lfs.2022.121278)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Maassen JA, ’T Hart LM, Van Essen E, Heine RJ, Nijpels G, Jahangir Tafrechi RS, Raap AK, Janssen GM & & Lemkes HH 2004 Mitochondrial diabetes: molecular mechanisms and clinical presentation. Diabetes 53(Supplement 1) S103–S109. (https://doi.org/10.2337/diabetes.53.2007.s103)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Merz KE, Hwang J, Zhou C, Veluthakal R, McCown EM, Hamilton A, Oh E, Dai W, Fueger PT, Jiang L, et al.2022 Enrichment of the exocytosis protein STX4 in skeletal muscle remediates peripheral insulin resistance and alters mitochondrial dynamics via Drp1. Nature Communications 13 424. (https://doi.org/10.1038/s41467-022-28061-w)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S, Lehar J, Puigserver P, Carlsson E, Ridderstrale M, Laurila E, et al.2003 PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nature Genetics 34 267–273. (https://doi.org/10.1038/ng1180)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Nisr RB & & Affourtit C 2014 Insulin acutely improves mitochondrial function of rat and human skeletal muscle by increasing coupling efficiency of oxidative phosphorylation. Biochimica et Biophysica Acta 1837 270–276. (https://doi.org/10.1016/j.bbabio.2013.10.012)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Parra V, Verdejo HE, Iglewski M, Del Campo A, Troncoso R, Jones D, Zhu Y, Kuzmicic J, Pennanen C, Lopez-Crisosto C, et al.2014 Insulin stimulates mitochondrial fusion and function in cardiomyocytes via the Akt-mTOR-NFκB-Opa-1 signaling pathway. Diabetes 63 75–88. (https://doi.org/10.2337/db13-0340)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Petersen KF, Befroy D, Dufour S, Dziura J, Ariyan C, Rothman DL, DiPietro L, Cline GW & & Shulman GI 2003 Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science 300 1140–1142. (https://doi.org/10.1126/science.1082889)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Pinho ACO, Santos D, Baldeiras I, Burgeiro A, Leal EC & & Carvalho E 2022 Mitochondrial respiration in thoracic perivascular adipose tissue of diabetic mice. Journal of Endocrinology 254 169–184. (https://doi.org/10.1530/JOE-21-0446)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Pinho ACO, Santos D, Oliveira PJ, Leal EC & & Carvalho E 2024 Real-time OXPHOS capacity analysis in wounded skin from diabetic mice: a pilot study. European Journal of Clinical Investigation 54 e14128. (https://doi.org/10.1111/eci.14128)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Piwkowska A, Rogacka D, Audzeyenka I, Kasztan M, Angielski S & & Jankowski M 2016 Intracellular calcium signaling regulates glomerular filtration barrier permeability: the role of the PKGIalpha-dependent pathway. FEBS Letters 590 1739–1748. (https://doi.org/10.1002/1873-3468.12228)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Piwkowska A, Rogacka D, Kasztan M, Angielski S & & Jankowski M 2013 Insulin increases glomerular filtration barrier permeability through dimerization of protein kinase G type Ialpha subunits. Biochimica et Biophysica Acta 1832 791–804. (https://doi.org/10.1016/j.bbadis.2013.02.011)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Quach CH, Jung KH, Lee JH, Park JW, Moon SH, Cho YS, Choe YS & & Lee KH 2016 Mild alkalization acutely triggers the Warburg effect by enhancing hexokinase activity via voltage-dependent anion channel binding. PLoS ONE 11 e0159529. (https://doi.org/10.1371/journal.pone.0159529)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Ren Z, Zhong H, Song C, Deng C, Hsieh HT, Liu W & & Chen G 2020 Insulin promotes mitochondrial respiration and survival through PI3K/AKT/GSK3 pathway in human embryonic stem cells. Stem Cell Reports 15 1362–1376. (https://doi.org/10.1016/j.stemcr.2020.10.008)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Ritov VB, Menshikova EV, Azuma K, Wood R, Toledo FG, Goodpaster BH, Ruderman NB & & Kelley DE 2010 Deficiency of electron transport chain in human skeletal muscle mitochondria in type 2 diabetes mellitus and obesity. American Journal of Physiology. Endocrinology and Metabolism 298 E49–E58. (https://doi.org/10.1152/ajpendo.00317.2009)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Samuel VT, Petersen KF & & Shulman GI 2010 Lipid-induced insulin resistance: unravelling the mechanism. Lancet 375 2267–2277. (https://doi.org/10.1016/S0140-6736(1060408-4)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Steil GM, Ader M, Moore DM, Rebrin K & & Bergman RN 1996 Transendothelial insulin transport is not saturable in vivo. No evidence for a receptor-mediated process. Journal of Clinical Investigation 97 1497–1503. (https://doi.org/10.1172/JCI118572)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Stirling DR, Swain-Bowden MJ, Lucas AM, Carpenter AE, Cimini BA & & Goodman A 2021 CellProfiler 4: improvements in speed, utility and usability. BMC Bioinformatics 22 433. (https://doi.org/10.1186/s12859-021-04344-9)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Stump CS, Short KR, Bigelow ML, Schimke JM & & Nair KS 2003 Effect of insulin on human skeletal muscle mitochondrial ATP production, protein synthesis, and mRNA transcripts. PNAS 100 7996–8001. (https://doi.org/10.1073/pnas.1332551100)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Sun Y, Cui S, Hou Y & & Yi F 2021 The updates of podocyte lipid metabolism in proteinuric kidney disease. Kidney Diseases 7 438–451. (https://doi.org/10.1159/000518132)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Sun YB, Qu X, Howard V, Dai L, Jiang X, Ren Y, Fu P, Puelles VG, Nikolic-Paterson DJ, Caruana G, et al.2015 Smad3 deficiency protects mice from obesity-induced podocyte injury that precedes insulin resistance. Kidney International 88 286–298. (https://doi.org/10.1038/ki.2015.121)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Szeto HH, Liu S, Soong Y, Alam N, Prusky GT & & Seshan SV 2016 Protection of mitochondria prevents high-fat diet-induced glomerulopathy and proximal tubular injury. Kidney International 90 997–1011. (https://doi.org/10.1016/j.kint.2016.06.013)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Wang L, Ishihara T, Ibayashi Y, Tatsushima K, Setoyama D, Hanada Y, Takeichi Y, Sakamoto S, Yokota S, Mihara K, et al.2015 Disruption of mitochondrial fission in the liver protects mice from diet-induced obesity and metabolic deterioration. Diabetologia 58 2371–2380. (https://doi.org/10.1007/s00125-015-3704-7)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Wang Y, Wang J, Tao SY, Liang Z, Xie R, Liu NN, Deng R, Zhang Y, Deng D & & Jiang G 2024 Mitochondrial damage-associated molecular patterns: a new insight into metabolic inflammation in type 2 diabetes mellitus. Diabetes/Metabolism Research and Reviews 40 e3733. (https://doi.org/10.1002/dmrr.3733)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Welsh GI, Hale LJ, Eremina V, Jeansson M, Maezawa Y, Lennon R, Pons DA, Owen RJ, Satchell SC, Miles MJ, et al.2010 Insulin signaling to the glomerular podocyte is critical for normal kidney function. Cell Metabolism 12 329–340. (https://doi.org/10.1016/j.cmet.2010.08.015)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Williams IM, Valenzuela FA, Kahl SD, Ramkrishna D, Mezo AR, Young JD, Wells KS & & Wasserman DH 2018 Insulin exits skeletal muscle capillaries by fluid-phase transport. Journal of Clinical Investigation 128 699–714. (https://doi.org/10.1172/JCI94053)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Wu C, Khan SA & & Lange AJ 2005 Regulation of glycolysis-role of insulin. Experimental Gerontology 40 894–899. (https://doi.org/10.1016/j.exger.2005.08.002)

  • Yang HM, Kim J, Shin D, Kim JY, You J, Lee HC, Jang HD & & Kim HS 2023 Resistin impairs mitochondrial homeostasis via cyclase-associated protein 1-mediated fission, leading to obesity-induced metabolic diseases. Metabolism: Clinical and Experimental 138 155343. (https://doi.org/10.1016/j.metabol.2022.155343)

    • PubMed
    • Search Google Scholar
    • Export Citation