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Dexamethasone upregulates mitochondrial Tom20, Tom70, and MnSOD through SGK1 in the kidney cells

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Abstract

Dexamethasone augments mitochondrial protein abundance. The translocase of the outer membrane (Tom) of mitochondria plays a major role in importing largely cytosolically synthesized proteins into mitochondria. We hypothesize that dexamethasone upregulates the Tom transport system, leading to increase of mitochondrial protein localization. Tom20 and Tom70 are the two major subunits. Dexamethasone increased Tom20 and Tom70 mRNA levels by 53 ± 11% and 25 ± 9% and mitochondrial protein abundance by 27 ± 7% and 25 ± 4% (p < 0.05 for all), respectively, in HEK293 cells. In parallel, dexamethasone elevated the SGK1 mRNA by 79 ± 17% and activity by 190 ± 42%, and mitochondrial protein level by 41 ± 2% (all p < 0.05) without significantly affecting the cytosol counterpart. The discovery of the effect of dexamethasone on SGK1 protein restricted in the mitochondria attracted us to examine the effect of the hormone on MnSOD, an enzyme with known mitochondrial localization and function. Similarly, dexamethasone significantly increased MnSOD transcripts by 67 ± 15% and protein level only in the mitochondria dose-dependently. Inhibition of SGK1 by GSK650394 and RNAi significantly attenuated the effects of the hormone on Tom20, Tom70, and MnSOD, indicating that SGK1 relays the effects of dexamethasone. Catalase inhibited the effects of dexamethasone on SGK1 and the subsequent effects of SGK1 on Tom20, Tom70, and MnSOD. Finally, knock-down of Tom20 and Tom70 by their siRNAs reduced dexamethasone-induced increases in the mitochondrial localization of SGK1 and MnSOD proteins. In conclusion, dexamethasone upregulates Tom20, Tom70, and MnSOD, and these effects are dependent on reactive oxygen species and SGK1. Dexamethasone-induced increases of SGK1 and MnSOD mitochondrial localization requires Tom20 and Tom70.

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Abbreviations

MnSOD:

Manganese superoxide dismutase

NDRG1:

N-myc downstream-regulated gene1

ROS:

Reactive oxygen species

SGK1:

Serum- and glucocorticoid-inducible kinase 1

Tom20:

Translocase of the outer membrane subunit 20

Tom70:

Translocase of the outer membrane subunit 70

References

  1. Alvarez de la Rosa D, Coric T, Todorovic N, Shao D, Wang T, Canessa CM (2003) Distribution and regulation of expression of serum- and glucocorticoid-induced kinase-1 in the rat kidney. J Physiol 551:455–466

    Article  CAS  Google Scholar 

  2. Bonvalet JP (1998) Regulation of sodium transport by steroid hormones. Kidney Int Suppl 65:S49–S56

    CAS  PubMed  Google Scholar 

  3. Buse P, Tran SH, Luther E, Phu PT, Aponte GW, Firestone GL (1999) Cell cycle and hormonal control of nuclear-cytoplasmic localization of the serum- and glucocorticoid-inducible protein kinase, Sgk, in mammary tumor cells. A novel convergence point of anti-proliferative and proliferative cell signaling pathways. J Biol Chem 274:7253–7263

    Article  CAS  Google Scholar 

  4. Choi HM, Jo SK, Kim SH, Lee JW, Cho E, Hyun YY, Cha JJ, Kang YS, Cha DR, Cho WY, Kim HK (2013) Glucocorticoids attenuate septic acute kidney injury. Biochem Biophys Res Commun 435:678–684

    Article  CAS  Google Scholar 

  5. Cordas E, Naray-Fejes-Toth A, Fejes-Toth G (2007) Subcellular location of serum- and glucocorticoid-induced kinase-1 in renal and mammary epithelial cells. Am J Physiol Cell Physiol 292:C1971–C1981

    Article  CAS  Google Scholar 

  6. Desquiret V, Gueguen N, Malthiery Y, Ritz P, Simard G (2008) Mitochondrial effects of dexamethasone imply both membrane and cytosolic-initiated pathways in HepG2 cells. Int J Biochem Cell Biol 40:1629–1641

    Article  CAS  Google Scholar 

  7. Djouadi F, Wijkhuisen A, Bastin J, Vilar J, Merlet-Benichou C (1993) Effect of glucocorticoids on mitochondrial oxidative enzyme and Na-K-ATPase activities in the rat proximal tubule and thick ascending limb of Henle. Ren Physiol Biochem 16:249–256

    CAS  PubMed  Google Scholar 

  8. Djouadi F, Bastin J, Kelly DP, Merlet-Benichou C (1996) Transcriptional regulation by glucocorticoids of mitochondrial oxidative enzyme genes in the developing rat kidney. Biochem J 315(Pt 2):555–562

    Article  CAS  Google Scholar 

  9. Dudek J, Rehling P, van der Laan M (2013) Mitochondrial protein import: common principles and physiological networks. Biochim Biophys Acta 1833:274–285

    Article  CAS  Google Scholar 

  10. Eldeeb MA, Ragheb MA, Esmaili M (2020) How does protein degradation regulate TOM machinery-dependent mitochondrial import? Curr Genet 66:501–505

  11. Engelsberg A, Kobelt F, Kuhl D (2006) The N-terminus of the serum- and glucocorticoid-inducible kinase Sgk1 specifies mitochondrial localization and rapid turnover. Biochem J 399:69–76

    Article  CAS  Google Scholar 

  12. Gerbeth C, Schmidt O, Rao S, Harbauer AB, Mikropoulou D, Opalinska M, Guiard B, Pfanner N, Meisinger C (2013) Glucose-induced regulation of protein import receptor Tom22 by cytosolic and mitochondria-bound kinases. Cell Metab 18:578–587

    Article  CAS  Google Scholar 

  13. Harbauer AB, Zahedi RP, Sickmann A, Pfanner N, Meisinger C (2014) The protein import machinery of mitochondria-a regulatory hub in metabolism, stress, and disease. Cell Metab 19:357–372

    Article  CAS  Google Scholar 

  14. Helms MN, Fejes-Toth G, Naray-Fejes-Toth A (2003) Hormone-regulated transepithelial Na+ transport in mammalian CCD cells requires SGK1 expression. Am J Physiol Renal Physiol 284:F480–F487

    Article  CAS  Google Scholar 

  15. Hernandez-Alvarez MI, Paz JC, Sebastian D, Munoz JP, Liesa M, Segales J, Palacin M, Zorzano A (2013) Glucocorticoid modulation of mitochondrial function in hepatoma cells requires the mitochondrial fission protein Drp1. Antioxid Redox Signal 19:366–378

    Article  CAS  Google Scholar 

  16. Hira S, Packialakshmi B, Zhou X (2019) EAE-induced upregulation of mitochondrial MnSOD is associated with increases of mitochondrial SGK1 and Tom20 protein in the mouse kidney cortex. J Physiol Sci 69:723–732

    Article  CAS  Google Scholar 

  17. Kadowaki T, Kitagawa Y (1988) Enhanced transcription of mitochondrial genes after growth stimulation and glucocorticoid treatment of Reuber hepatoma H-35. FEBS Lett 233:51–56

    Article  CAS  Google Scholar 

  18. Kiersztan A, Trojan N, Tempes A, Nalepa P, Sitek J, Winiarska K, Usarek M (2017) DHEA supplementation to dexamethasone-treated rabbits alleviates oxidative stress in kidney-cortex and attenuates albuminuria. J Steroid Biochem Mol Biol 174:17–26

    Article  CAS  Google Scholar 

  19. Kim MS, Ramakrishna S, Lim KH, Kim JH, Baek KH (2011) Protein stability of mitochondrial superoxide dismutase SOD2 is regulated by USP36. J Cell Biochem 112:498–508

    Article  CAS  Google Scholar 

  20. Kumar S, Allen DA, Kieswich JE, Patel NS, Harwood S, Mazzon E, Cuzzocrea S, Raftery MJ, Thiemermann C, Yaqoob MM (2009) Dexamethasone ameliorates renal ischemia-reperfusion injury. J Am Soc Nephrol 20:2412–2425

    Article  CAS  Google Scholar 

  21. Lang F, Artunc F, Vallon V (2009) The physiological impact of the serum and glucocorticoid-inducible kinase SGK1. Curr Opin Nephrol Hypertens 18:439–448

    Article  CAS  Google Scholar 

  22. Leong ML, Maiyar AC, Kim B, O'Keeffe BA, Firestone GL (2003) Expression of the serum- and glucocorticoid-inducible protein kinase, Sgk, is a cell survival response to multiple types of environmental stress stimuli in mammary epithelial cells. J Biol Chem 278:5871–5882

    Article  CAS  Google Scholar 

  23. Macconi D, Zanoli AF, Orisio S, Longaretti L, Magrini L, Rota S, Radice A, Pozzi C, Remuzzi G (1993) Methylprednisolone normalizes superoxide anion production by polymorphs from patients with ANCA-positive vasculitides. Kidney Int 44:215–220

    Article  CAS  Google Scholar 

  24. Mansley MK, Watt GB, Francis SL, Walker DJ, Land SC, Bailey MA, Wilson SM (2016) Dexamethasone and insulin activate serum and glucocorticoid-inducible kinase 1 (SGK1) via different molecular mechanisms in cortical collecting duct cells. Physiol Rep 4: e12792

  25. Nakai A, Shibazaki Y, Taniuchi Y, Oya A, Asakura H, Koshino T, Araki T (2002) Effect of dexamethasone on mitochondrial maturation in the fetal rat brain. Am J Obstet Gynecol 186:574–578

    Article  CAS  Google Scholar 

  26. O'Keeffe BA, Cilia S, Maiyar AC, Vaysberg M, Firestone GL (2013) The serum- and glucocorticoid-induced protein kinase-1 (Sgk-1) mitochondria connection: identification of the IF-1 inhibitor of the F(1)F(0)-ATPase as a mitochondria-specific binding target and the stress-induced mitochondrial localization of endogenous Sgk-1. Biochimie 95:1258–1265

    Article  CAS  Google Scholar 

  27. Packialakshmi B, Zhou X (2018) Experimental autoimmune encephalomyelitis (EAE) up-regulates the mitochondrial activity and manganese superoxide dismutase (MnSOD) in the mouse renal cortex. PLoS One 13:e0196277

    Article  Google Scholar 

  28. Parajuli N, Marine A, Simmons S, Saba H, Mitchell T, Shimizu T, Shirasawa T, MacMillan-Crow LA (2011) Generation and characterization of a novel kidney-specific manganese superoxide dismutase knockout mouse. Free Radic Biol Med

  29. Psarra AM, Solakidi S, Sekeris CE (2006) The mitochondrion as a primary site of action of steroid and thyroid hormones: presence and action of steroid and thyroid hormone receptors in mitochondria of animal cells. Mol Cell Endocrinol 246:21–33

    Article  CAS  Google Scholar 

  30. Schmidt O, Harbauer AB, Rao S, Eyrich B, Zahedi RP, Stojanovski D, Schonfisch B, Guiard B, Sickmann A, Pfanner N, Meisinger C (2011) Regulation of mitochondrial protein import by cytosolic kinases. Cell 144:227–239

    Article  CAS  Google Scholar 

  31. Srivastava S, Savanur MA, Sinha D, Birje A, Vigneshwaran R, Saha PP, D’Silva P (2017) Regulation of mitochondrial protein import by the nucleotide exchange factors GrpEL1 and GrpEL2 in human cells. J Biol Chem 292:18075–18090

    Article  CAS  Google Scholar 

  32. Valentine JF, Nick HS (1994) Glucocorticoids repress basal and stimulated manganese superoxide dismutase levels in rat intestinal epithelial cells. Gastroenterology 107:1662–1670

    Article  CAS  Google Scholar 

  33. Wang D, Zhang H, Lang F, Yun CC (2007) Acute activation of NHE3 by dexamethasone correlates with activation of SGK1 and requires a functional glucocorticoid receptor. Am J Physiol Cell Physiol 292:C396–C404

    Article  CAS  Google Scholar 

  34. Webster MK, Goya L, Ge Y, Maiyar AC, Firestone GL (1993) Characterization of sgk, a novel member of the serine/threonine protein kinase gene family which is transcriptionally induced by glucocorticoids and serum. Mol Cell Biol 13:2031–2040

    Article  CAS  Google Scholar 

  35. Wispe JR, Clark JC, Burhans MS, Kropp KE, Korfhagen TR, Whitsett JA (1989) Synthesis and processing of the precursor for human mangano-superoxide dismutase. Biochim Biophys Acta 994:30–36

    Article  CAS  Google Scholar 

  36. Yoshioka T, Kawamura T, Meyrick BO, Beckman JK, Hoover RL, Yoshida H, Ichikawa I (1994) Induction of manganese superoxide dismutase by glucocorticoids in glomerular cells. Kidney Int 45:211–219

    Article  CAS  Google Scholar 

  37. Yun CC, Chen Y, Lang F (2002) Glucocorticoid activation of Na(+)/H(+) exchanger isoform 3 revisited. The roles of SGK1 and NHERF2. J Biol Chem 277:7676–7683

    Article  CAS  Google Scholar 

  38. Zhou X, Ferraris JD, Cai Q, Agarwal A, Burg MB (2005) Increased reactive oxygen species contribute to high NaCl-induced activation of the osmoregulatory transcription factor TonEBP/OREBP. Am J Physiol Renal Physiol 289:F377–F385

    Article  CAS  Google Scholar 

  39. Zhou X, Gallazzini M, Burg MB, Ferraris JD (2010) Contribution of SHP-1 protein tyrosine phosphatase to osmotic regulation of the transcription factor TonEBP/OREBP. ProcNatlAcadSciUSA 107:7072–7077

    Article  CAS  Google Scholar 

  40. Zhou X, Packialakshmi B, Xiao Y, Nurmukhambetova S, Lees JR (2017) Progression of experimental autoimmune encephalomyelitis is associated with up-regulation of major sodium transporters in the mouse kidney cortex under a normal salt diet. Cell Immunol 317:18–25

    Article  CAS  Google Scholar 

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Funding

This work was funded in part by the grant (MED-83-3923) from the collaborative health initiative research program between the National Heart Lung and Blood Institute and the Henry Jackson Foundation for the Advancement of Military Medicine and a Uniformed Services University education grant. Authors thank Dr. Louis Pangaro for his help in obtaining the education grant.

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Authors and Affiliations

  1. Department of Medicine, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD, 20814, USA

    Sharanpreet Hira, Balamurugan Packialakshmi, Esther Tang & Xiaoming Zhou

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  1. Sharanpreet Hira
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  2. Balamurugan Packialakshmi
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  3. Esther Tang
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  4. Xiaoming Zhou
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Correspondence to Xiaoming Zhou.

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Key Points

• The Tom mitochondrial translocase is upregulated by dexamethasone through activation of SGK1.

• Dexamethasone induces Tom-dependent increases of mitochondrial SGK1 and MnSOD.

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Hira, S., Packialakshmi, B., Tang, E. et al. Dexamethasone upregulates mitochondrial Tom20, Tom70, and MnSOD through SGK1 in the kidney cells. J Physiol Biochem 77, 1–11 (2021). https://doi.org/10.1007/s13105-020-00773-x

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  • DOI: https://doi.org/10.1007/s13105-020-00773-x

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