Skip to main content

Advertisement

Log in

Biodistribution of Intravenously Transplanted Mitochondria Conjugated with Graphene Quantum Dots in Diabetic Rats

  • Research
  • Published:
Journal of Fluorescence Aims and scope Submit manuscript

Abstract

Mitochondria transplantation has emerged as a successful therapeutic modality to treat several degenerative diseases. However, the biodistribution of transplanted mitochondria has not been well studied. We investigated the ex-vivo systemic biodistribution and therapeutic efficacy of intravenously transplanted graphene quantum dots (GQDs) conjugated to isolated mitochondria (Mt-GQDs) in diabetic rat tissues. The results revealed that Mt-GQDs facilitate the tracking of transplanted mitochondria without affecting their therapeutic efficacy. It is compelling to note that Mt-GQDs and isolated mitochondria show comparable therapeutic efficacies in decreasing blood glucose levels, oxidative stress, inflammatory gene expressions, and restoration of different mitochondrial functions in pancreatic tissues of diabetic rats. In addition, histological section examination under a fluorescence microscope demonstrated the localization of Mt-GQDs in multiple tissues of diabetic rats. In conclusion, this study indicates that Mt-GQDs provide an effective mitochondrial transplantation tracking modality.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Data Availability

Data would be made available on request.

Abbreviations

GQDs:

Graphene Quantum Dots

Mt-GQDs:

Mitochondria conjugated Graphene Quantum Dots

STZ:

Streptozotocin

NCD:

Normal Chow Diet

TEM:

Transmission electron microscope

FTIR:

Fourier transform infrared

PDI:

Polydispersity Index

PEG:

Polyethylene glycol

GFP:

Green fluorescent protein

TBARS:

Thiobarbituric acid reactive substances

NO:

Nitric oxide

SOD:

Superoxide dismutase

CAT:

Catalase

GSH:

And reduced glutathione

ATP:

Adenosine triphosphate

PGC1-α:

Peroxisome proliferator-activated receptor-gamma coactivator

NF-kB:

Nuclear factor kappa

IL-6:

Interleukin

References

  1. Gouspillou G, Hepple RT (2016) Editorial: Mitochondria in Skeletal Muscle Health, Aging and Diseases. Front Physiol 7:446. https://doi.org/10.3389/fphys.2016.00446

    Article  PubMed  PubMed Central  Google Scholar 

  2. Braczko A, Kutryb-Zajac B, Jedrzejewska A et al (2022) Cardiac Mitochondria Dysfunction in Dyslipidemic mice. Int J Mol Sci 23(19):11488. https://doi.org/10.3390/ijms231911488

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Witte ME, Mahad DJ, Lassmann H, van Horssen J (2014) Mitochondrial dysfunction contributes to neurodegeneration in multiple sclerosis. Trends Mol Med 20(3):179–187. https://doi.org/10.1016/j.molmed.2013.11.007

    Article  PubMed  Google Scholar 

  4. Wang ZH, Chen L, Li W, Chen L, Wang YP (2022) Mitochondria transfer and transplantation in human health and Diseases. Mitochondrion 65:80–87. https://doi.org/10.1016/j.mito.2022.05.002

    Article  CAS  PubMed  Google Scholar 

  5. Paliwal S, Chaudhuri R, Agrawal A, Mohanty S (2018) Regenerative abilities of mesenchymal stem cells through mitochondrial transfer. J Biomed Sci 25(1):31. https://doi.org/10.1186/s12929-018-0429-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Liu Z, Sun Y, Qi Z, Cao L, Ding S (2022) Mitochondrial transfer/transplantation: an emerging therapeutic approach for multiple Diseases. Cell & Bioscience 12(1):66. https://doi.org/10.1186/s13578-022-00805-7

    Article  CAS  Google Scholar 

  7. Gollihue JL, Patel SP, Eldahan KC, Cox DH, Donahue RR, Taylor BK, Sullivan PG, Rabchevsky AG (2018) Effects of Mitochondrial Transplantation on Bioenergetics, Cellular Incorporation, and functional recovery after spinal cord Injury. J Neurotrauma 35(15):1800–1818. https://doi.org/10.1089/neu.2017.5605

    Article  PubMed  PubMed Central  Google Scholar 

  8. Konari N, Nagaishi K, Kikuchi S, Fujimiya M (2019) Mitochondria transfer from mesenchymal stem cells structurally and functionally repairs renal proximal tubular epithelial cells in diabetic Nephropathy in vivo. Sci Rep 9(1):5184. https://doi.org/10.1038/s41598-019-40163-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Moskowitzova K, Orfany A, Liu K (2020) Mitochondrial transplantation enhances murine lung viability and recovery after ischemia-reperfusion injury. Am J Physiol Lung Cell Mol Physiol 318(1):L78–L88. https://doi.org/10.1152/ajplung.00221.2019

    Article  CAS  PubMed  Google Scholar 

  10. McCully JD, Cowan DB, Pacak CA, Toumpoulis IK, Dayalan H, Levitsky S (2009) Injection of isolated mitochondria during early reperfusion for cardioprotection. Am J Physiol Heart Circ Physiol 296(1):H94–H105. https://doi.org/10.1152/ajpheart.00567.2008

    Article  CAS  PubMed  Google Scholar 

  11. Masuzawa A, Black KM, Pacak (2013) Transplantation of autologously derived mitochondria protects the heart from ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 304(7):H966–H982. https://doi.org/10.1152/ajpheart.00883.2012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Huang PJ, Kuo CC, Lee HC, Shen CI, Cheng FC, Wu SF, Chang JC, Pan HC, Lin SZ, Liu CS, Su HL (2016) Transferring Xenogenic Mitochondria provides neural Protection against ischemic stress in ischemic rat brains. Cell Transplant 25(5):913–927. https://doi.org/10.3727/096368915X689785

    Article  CAS  PubMed  Google Scholar 

  13. Hayashida K, Takegawa R, Endo Y (2023) Exogenous mitochondrial transplantation improves survival and neurological outcomes after resuscitation from Cardiac Arrest. BMC Med 21(1):56. https://doi.org/10.1186/s12916-023-02759-0

    Article  PubMed  PubMed Central  Google Scholar 

  14. Doulamis IP, Guariento A, Duignan T, Orfany A, Kido T, Zurakowski D, Del Nido PJ, McCully JD (2020) Mitochondrial transplantation for myocardial protection in diabetic hearts. Eur J cardio-thoracic Surgery: Official J Eur Association Cardio-thoracic Surg 57(5):836–845. https://doi.org/10.1093/ejcts/ezz326

    Article  Google Scholar 

  15. Cowan DB, Yao R, Akurathi V et al (2016) Intracoronary Delivery of Mitochondria to the ischemic heart for Cardioprotection. PLoS ONE 11(8):e0160889. https://doi.org/10.1371/journal.pone.0160889

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Liu JH, Li RS, Yuan B, Wang J, Li YF, Huang CZ (2018) Mitochondria-targeting single-layered graphene quantum dots with dual recognition sites for ATP imaging in living cells. Nanoscale 10(36):17402–17408. https://doi.org/10.1039/c8nr06061d

    Article  CAS  PubMed  Google Scholar 

  17. Lv O, Tao Y, Qin Y, Chen C, Pan Y, Deng L, Liu L, Kong Y (2016) Highly fluorescent and morphology-controllable graphene quantum dots-chitosan hybrid xerogels for in vivo imaging and pH-sensitive drug carrier. Mater Sci Eng C Mater Biol Appl 67:478–485. https://doi.org/10.1016/j.msec.2016.05.031

    Article  CAS  PubMed  Google Scholar 

  18. Michalet X, Pinaud FF, Bentolila LA et al (2005) Quantum dots for live cells, in vivo imaging, and diagnostics. Sci (New York N Y) 307(5709):538–544. https://doi.org/10.1126/science.1104274

    Article  CAS  Google Scholar 

  19. Lin YS, Chen Y, Tsai YH, Tseng SH, Lin KS (2021) In vivo imaging of neuroblastomas using GD2-targeting graphene quantum dots. J Pediatr Surg 56(7):1227–1232. https://doi.org/10.1016/j.jpedsurg.2021.03.035

    Article  PubMed  Google Scholar 

  20. Valimukhametova AR, Zub OS, Lee BH, Fannon O, Nguyen S, Gonzalez-Rodriguez R, Akkaraju GR, Naumov AV (2022) Dual-Mode Fluorescence/Ultrasound imaging with Biocompatible Metal-Doped Graphene Quantum dots. ACS Biomaterials Science & Engineering 8(11):4965–4975. https://doi.org/10.1021/acsbiomaterials.2c00794

    Article  CAS  Google Scholar 

  21. Yan H, Wang Q, Wang J, Shang W, Xiong Z, Zhao L, Sun X, Tian J, Kang F, Yun SH (2023) Planted Graphene Quantum dots for targeted, Enhanced Tumor Imaging and Long-Term Visualization of Local Pharmacokinetics. Adv Mater (Deerfield Beach Fla) 35(15):e2210809. https://doi.org/10.1002/adma.202210809

    Article  CAS  Google Scholar 

  22. Walton-Raaby M, Woods R, Kalyaanamoorthy S (2023) Investigating the Theranostic Potential of Graphene Quantum Dots in Alzheimer’s Disease. Int J Mol Sci 24(11):9476. https://doi.org/10.3390/ijms24119476

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Choppadandi M, Guduru AT, Gondaliya P, Arya N, Kalia K, Kumar H, Kapusetti G (2021) Structural features regulated photoluminescence intensity and cell internalization of carbon and graphene quantum dots for bioimaging. Mater Sci Eng C Mater Biol Appl 129:112366. https://doi.org/10.1016/j.msec.2021.112366

    Article  CAS  PubMed  Google Scholar 

  24. Fan Z, Nie Y, Wei Y, Zhao J, Liao X, Zhang J (2019) Facile and large-scale synthesis of graphene quantum dots for selective targeting and imaging of cell nucleus and mitochondria. Mater Sci Eng C Mater Biol Appl 103:109824. https://doi.org/10.1016/j.msec.2019.109824

    Article  CAS  PubMed  Google Scholar 

  25. Aizik G, Waiskopf N, Agbaria M, Levi-Kalisman Y, Banin U, Golomb G (2017) Delivery of Liposomal Quantum Dots via monocytes for Imaging of Inflamed tissue. ACS Nano 11(3):3038–3051. https://doi.org/10.1021/acsnano.7b00016

    Article  CAS  PubMed  Google Scholar 

  26. Ji Y, Li YM, Seo JG, Jang TS, Knowles JC, Song SH, Lee JH (2021) Biological potential of polyethylene glycol (PEG)-Functionalized Graphene Quantum dots in in vitro neural Stem/Progenitor cells. Nanomaterials (Basel Switzerland) 11(6):1446. https://doi.org/10.3390/nano11061446

    Article  CAS  PubMed  Google Scholar 

  27. Li WQ, Wang Z, Hao S, Sun L, Nisic M, Cheng G, Zhu C, Wan Y, Ha L, Zheng SY (2018) Mitochondria-based aircraft carrier enhances in vivo imaging of carbon quantum dots and delivery of anticancer drug. Nanoscale 10(8):3744–3752. https://doi.org/10.1039/c7nr08816g

    Article  CAS  PubMed  Google Scholar 

  28. Nurunnabi M, Khatun Z, Huh KM, Park SY, Lee DY, Cho KJ, Lee YK (2013) In vivo biodistribution and toxicology of carboxylated graphene quantum dots. ACS Nano 7(8):6858–6867. https://doi.org/10.1021/nn402043c

    Article  CAS  PubMed  Google Scholar 

  29. Lu F, Zhou YH, Wu LH, Qian J, Cao S, Deng YF, Chen Y (2019) Highly fluorescent nitrogen-doped graphene quantum dots’ synthesis and their applications as fe (III) ions sensor. Int J Opt,

  30. Clayton DA, Shadel GS (2014) Isolation of mitochondria from tissue culture cells. Cold Spring Harbor Protoc 2014(10). https://doi.org/10.1101/pdb.prot080002. pdb.prot080002

  31. Fu A, Shi X, Zhang H, Fu B (2017) Mitotherapy for fatty liver by Intravenous Administration of Exogenous Mitochondria in male mice. Front Pharmacol 8:241. https://doi.org/10.3389/fphar.2017.00241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Verma K, Makwana S, Paliwal S, Paliwal V, Jain S, Paliwal S, Sharma S (2022) Simvastatin ameliorates oxidative stress levels in HepG2 cells and hyperlipidemic rats. Curr Res Pharmacol drug Discovery 3:100088. https://doi.org/10.1016/j.crphar.2022.100088

    Article  Google Scholar 

  33. Barrientos A, Fontanesi F, Díaz F (2009) Evaluation of the mitochondrial respiratory chain and oxidative phosphorylation system using polarography and spectrophotometric enzyme assays. Curr Protocols Hum Genet Chap 19. https://doi.org/10.1002/0471142905.hg1903s63. Unit19.3

  34. Paliwal S, Chaudhuri R, Agrawal A, Mohanty S (2018) Human tissue-specific MSCs demonstrate differential mitochondria transfer abilities that may determine their regenerative abilities. Stem Cell Res Ther 9(1):298. https://doi.org/10.1186/s13287-018-1012-0

    Article  PubMed  PubMed Central  Google Scholar 

  35. McCully JD, Cowan DB, Emani SM, Del Nido PJ (2017) Mitochondrial transplantation: from animal models to clinical use in humans. Mitochondrion 34:127–134. https://doi.org/10.1016/j.mito.2017.03.004

    Article  CAS  PubMed  Google Scholar 

  36. Murphy MP (2008) Targeting lipophilic cations to mitochondria. Biochim Biophys Acta 1777(7–8):1028–1031. https://doi.org/10.1016/j.bbabio.2008.03.029

    Article  CAS  PubMed  Google Scholar 

  37. Ayilliath SK, Nair SR, Lakshmi GC, Kunnatheery S (2021) Functionalised Graphene Quantum Dots for Cholesterol Detection in human blood serum. J Fluoresc 31(3):847–852. https://doi.org/10.1007/s10895-021-02712-5

    Article  CAS  PubMed  Google Scholar 

  38. Hong GL, Zhao HL, Deng HH, Yang HJ, Peng HP, Liu YH, Chen W (2018) Fabrication of ultra-small monolayer graphene quantum dots by pyrolysis of trisodium citrate for fluorescent cell imaging. Int J Nanomed 13:4807–4815. https://doi.org/10.2147/IJN.S168570

    Article  CAS  Google Scholar 

  39. Qiu X, Zhu X, Su X, Xu M, Yuan W, Liu Q, Xue M, Liu Y, Feng W, Li F (2019) Near-Infrared Upconversion Luminescence and Bioimaging In Vivo Based on Quantum Dots. Advanced science (Weinheim, Baden-Wurttemberg, Germany), 6(5), 1801834. https://doi.org/10.1002/advs.201801834

  40. Doulamis IP, Nomoto RS, Tzani A, Hong X, Duignan T, Celik A, Del Nido PJ, McCully JD (2022) Transcriptomic and proteomic pathways of diabetic and non-diabetic mitochondrial transplantation. Sci Rep 12(1):22101. https://doi.org/10.1038/s41598-022-25858-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Wu X, Tian F, Wang W, Chen J, Wu M, Zhao JX (2013) Fabrication of highly fluorescent graphene quantum dots using L-glutamic acid for in vitro/in vivo imaging and sensing. J Mater Chem C 1(31):4676–4684. https://doi.org/10.1039/C3TC30820K

    Article  CAS  Google Scholar 

  42. Fiori F, Moukham H, Olia F, Piras D, Ledda S, Salis A, Stagi L, Malfatti L, Innocenzi P (2022) Highly Photostable Carbon dots from Citric Acid for Bioimaging. Mater (Basel Switzerland) 15(7):2395. https://doi.org/10.3390/ma15072395

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We would like to thank Science and Engineering Research Board, SERB, SRG grant (SRG/2019/002105), Govt. of India and Banasthali Vidyapith for providing funds to support the research.

Funding

We would like to thank Science and Engineering Research Board (SERB), Govt. of India for funding through Start Up Research Grant (SRG), File Number: SRG/2019/002105 granted to Dr. Swati Paliwal.

Author information

Authors and Affiliations

Authors

Contributions

P.M carried synthesis, characterization of nanoparticles and animal model work, J.P performed biochemical assays. S.P conceptualized the idea and supervised the study. All the authors contributed to writing and reviewing the manuscript.

Corresponding author

Correspondence to Swati Paliwal.

Ethics declarations

Consent for Publication

The corresponding author on behalf of all the authors authorizes the publishers to publish the data after acceptance.

Consent to Participate

Not Applicable.

Ethics Declaration Statement

The approval for animal work was received from the Institutional Animal Ethics Committee (BV/IAEC/74/2021) at Banasthali Vidyapith, Rajasthan, India-304022.

Competing Interests

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic Supplementary Material

Below is the link to the electronic supplementary material.

Supplementary Material 1

Supplementary Material 2

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mudgal, P., Pareek, J. & Paliwal, S. Biodistribution of Intravenously Transplanted Mitochondria Conjugated with Graphene Quantum Dots in Diabetic Rats. J Fluoresc (2023). https://doi.org/10.1007/s10895-023-03480-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s10895-023-03480-0

Keywords

Navigation