Mitochondrial Transplantation Reduces Lower Limb Ischemia-reperfusion Injury by Increasing Skeletal Muscle Energy and Adipocyte Browning

Overview

Journal Mol Ther Methods Clin Dev

Publisher Cell Press

Date 2023 Nov 29

PMID 38027061

Authors

Jiaqi Zeng

Jianing Liu

Haiya Ni

Ling Zhang

Jun Wang

Yazhou Li

Wentao Jiang

Ziyu Wu

Min Zhou

Affiliations

Soon will be listed here.

Abstract

Recent studies have shown that mitochondrial transplantation can repair lower limb IRI, but the underlying mechanism of the repair effect remains unclear. In this study, we found that in addition to being taken up by skeletal muscle cells, human umbilical cord mesenchymal stem cells (hMSCs)-derived mitochondria were also taken up by adipocytes, which was accompanied by an increase in optic atrophy 1 (OPA1) and uncoupling protein 1. Transplantation of hMSCs-derived mitochondria could not only supplement the original damaged mitochondrial function of skeletal muscle, but also promote adipocyte browning by increasing the expression of OPA1. In this process, mitochondrial transplantation can reduce cell apoptosis and repair muscle tissue, which promotes the recovery of motor function . To the best of our knowledge, there is no study on the therapeutic mechanism of mitochondrial transplantation from this perspective, which could provide a theoretical basis.

Citing Articles

Engineered mitochondria in diseases: mechanisms, strategies, and applications.

Li M, Wu L, Si H, Wu Y, Liu Y, Zeng Y Signal Transduct Target Ther. 2025; 10(1):71.

PMID: 40025039 PMC: 11873319. DOI: 10.1038/s41392-024-02081-y.

A Circular Network of Coregulated L-Threonine and L-Tryptophan Metabolism Dictates Acute Lower Limb Ischemic Injury.

Li L, Xiao C, Liu H, Chen S, Tang Y, Zhou H Int J Med Sci. 2024; 21(12):2402-2413.

PMID: 39310266 PMC: 11413896. DOI: 10.7150/ijms.102177.

Restoring Mitochondrial Function and Muscle Satellite Cell Signaling: Remedies against Age-Related Sarcopenia.

Marzetti E, Lozanoska-Ochser B, Calvani R, Landi F, Coelho-Junior H, Picca A Biomolecules. 2024; 14(4).

PMID: 38672432 PMC: 11048011. DOI: 10.3390/biom14040415.

Mitochondria in the Central Nervous System in Health and Disease: The Puzzle of the Therapeutic Potential of Mitochondrial Transplantation.

Tripathi K, Ben-Shachar D Cells. 2024; 13(5.

PMID: 38474374 PMC: 10930936. DOI: 10.3390/cells13050410.

Can mitochondria brown the lower-limb adipocytes?.

Doulamis I, Tzani A Mol Ther Methods Clin Dev. 2024; 32(1):101181.

PMID: 38282897 PMC: 10818182. DOI: 10.1016/j.omtm.2023.101181.

References

Bean C, Audano M, Varanita T, Favaretto F, Medaglia M, Gerdol M . The mitochondrial protein Opa1 promotes adipocyte browning that is dependent on urea cycle metabolites. Nat Metab. 2021; 3(12):1633-1647. DOI: 10.1038/s42255-021-00497-2. View

Wang Y, Liu S, Yan Y, Li S, Tong H . SPARCL1 promotes C2C12 cell differentiation via BMP7-mediated BMP/TGF-β cell signaling pathway. Cell Death Dis. 2019; 10(11):852. PMC: 6838091. DOI: 10.1038/s41419-019-2049-4. View

Sun J, Jessica Lo H, Fan L, Yiu T, Shakoor A, Li G . High-efficiency quantitative control of mitochondrial transfer based on droplet microfluidics and its application on muscle regeneration. Sci Adv. 2022; 8(33):eabp9245. PMC: 9385153. DOI: 10.1126/sciadv.abp9245. View

Kawamura I, Takemura G, Kanamori H, Takeyama T, Kawaguchi T, Tsujimoto A . Repeated phlebotomy augments angiogenesis to improve blood flow in murine ischemic legs. Am J Physiol Heart Circ Physiol. 2010; 299(2):H372-8. DOI: 10.1152/ajpheart.00035.2010. View

Shadel G, Horvath T . Mitochondrial ROS signaling in organismal homeostasis. Cell. 2015; 163(3):560-9. PMC: 4634671. DOI: 10.1016/j.cell.2015.10.001. View

Li H, Wang C, He T, Zhao T, Chen Y, Shen Y . Mitochondrial Transfer from Bone Marrow Mesenchymal Stem Cells to Motor Neurons in Spinal Cord Injury Rats via Gap Junction. Theranostics. 2019; 9(7):2017-2035. PMC: 6485285. DOI: 10.7150/thno.29400. View

Pereira R, Marti A, Olvera A, Tadinada S, Bjorkman S, Weatherford E . OPA1 deletion in brown adipose tissue improves thermoregulation and systemic metabolism via FGF21. Elife. 2021; 10. PMC: 8128440. DOI: 10.7554/eLife.66519. View

Dai D, Hsieh E, Chen T, Menendez L, Basisty N, Tsai L . Global proteomics and pathway analysis of pressure-overload-induced heart failure and its attenuation by mitochondrial-targeted peptides. Circ Heart Fail. 2013; 6(5):1067-76. PMC: 3856238. DOI: 10.1161/CIRCHEARTFAILURE.113.000406. View

Duehrkop C, Banz Y, Spirig R, Miescher S, Nolte M, Spycher M . C1 esterase inhibitor reduces lower extremity ischemia/reperfusion injury and associated lung damage. PLoS One. 2013; 8(8):e72059. PMC: 3753343. DOI: 10.1371/journal.pone.0072059. View

10.

Lynn E, Lu Z, Minerbi D, Sack M . The regulation, control, and consequences of mitochondrial oxygen utilization and disposition in the heart and skeletal muscle during hypoxia. Antioxid Redox Signal. 2007; 9(9):1353-61. DOI: 10.1089/ars.2007.1700. View

11.

Chen W, Shi K, Chu B, Wei X, Qian Z . Mitochondrial Surface Engineering for Multidrug Resistance Reversal. Nano Lett. 2019; 19(5):2905-2913. DOI: 10.1021/acs.nanolett.8b05188. View

12.

Masuzawa A, Black K, Pacak C, Ericsson M, Barnett R, Drumm C . Transplantation of autologously derived mitochondria protects the heart from ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol. 2013; 304(7):H966-82. PMC: 3625892. DOI: 10.1152/ajpheart.00883.2012. View

13.

Kim M, Sung B, Kang Y, Kim D, Lee Y, Hwang S . The combination of ursolic acid and leucine potentiates the differentiation of C2C12 murine myoblasts through the mTOR signaling pathway. Int J Mol Med. 2014; 35(3):755-62. DOI: 10.3892/ijmm.2014.2046. View

14.

Yokomori N, Tawata M, Onaya T . DNA demethylation modulates mouse leptin promoter activity during the differentiation of 3T3-L1 cells. Diabetologia. 2002; 45(1):140-8. DOI: 10.1007/s125-002-8255-4. View

15.

Lin H, Liu S, Lai H, Lai I . Isolated mitochondria infusion mitigates ischemia-reperfusion injury of the liver in rats. Shock. 2013; 39(3):304-10. DOI: 10.1097/SHK.0b013e318283035f. View

16.

Whitson J, Bitto A, Zhang H, Sweetwyne M, Coig R, Bhayana S . SS-31 and NMN: Two paths to improve metabolism and function in aged hearts. Aging Cell. 2020; 19(10):e13213. PMC: 7576234. DOI: 10.1111/acel.13213. View

17.

Liu J, Liu X, Wu M, Qi G, Liu B . Engineering Living Mitochondria with AIE Photosensitizer for Synergistic Cancer Cell Ablation. Nano Lett. 2020; 20(10):7438-7445. DOI: 10.1021/acs.nanolett.0c02778. View

18.

Moskowitzova K, Orfany A, Liu K, Ramirez-Barbieri G, Thedsanamoorthy J, Yao R . Mitochondrial transplantation enhances murine lung viability and recovery after ischemia-reperfusion injury. Am J Physiol Lung Cell Mol Physiol. 2019; 318(1):L78-L88. PMC: 6985877. DOI: 10.1152/ajplung.00221.2019. View

19.

Olichon A, Baricault L, Gas N, Guillou E, Valette A, Belenguer P . Loss of OPA1 perturbates the mitochondrial inner membrane structure and integrity, leading to cytochrome c release and apoptosis. J Biol Chem. 2003; 278(10):7743-6. DOI: 10.1074/jbc.C200677200. View

20.

Acin-Perez R, Petcherski A, Veliova M, Benador I, Assali E, Colleluori G . Recruitment and remodeling of peridroplet mitochondria in human adipose tissue. Redox Biol. 2021; 46:102087. PMC: 8377484. DOI: 10.1016/j.redox.2021.102087. View