The Role and Mechanism of Mitochondrial Ferroptosis in Uremic Toxin-Associated Myocardial Injury

Yaping ZHOU; Fangfang DI; Wei WANG

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Yaping ZHOU, Fangfang DI, Wei WANG. The Role and Mechanism of Mitochondrial Ferroptosis in Uremic Toxin-Associated Myocardial Injury[J]. Journal of Kunming Medical University.

Citation:

Yaping ZHOU, Fangfang DI, Wei WANG. The Role and Mechanism of Mitochondrial Ferroptosis in Uremic Toxin-Associated Myocardial Injury[J]. Journal of Kunming Medical University.

Yaping ZHOU, Fangfang DI, Wei WANG. The Role and Mechanism of Mitochondrial Ferroptosis in Uremic Toxin-Associated Myocardial Injury[J]. Journal of Kunming Medical University.

Citation:

Yaping ZHOU, Fangfang DI, Wei WANG. The Role and Mechanism of Mitochondrial Ferroptosis in Uremic Toxin-Associated Myocardial Injury[J]. Journal of Kunming Medical University.

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The Role and Mechanism of Mitochondrial Ferroptosis in Uremic Toxin-Associated Myocardial Injury

Department of Emergency and Critical Care Medicine，Langfang People’s Hospital，Langfang Hebei 065000，China

Received Date: 2025-08-12

Abstract

Abstract

Objective To investigate the role of the uremic toxin indoxyl sulfate （IS） in myocardial injury in chronic kidney disease （CKD） rats and to elucidate the mechanism of mediating ferroptosis through the mitochondrial pathway. Methods A CKD model was established using the 5/6 nephrectomy method. Rats were randomly divided into five groups: sham-operated, CKD, IS, CKD+IS, and CKD+IS+ferroptosis inhibitor Ferrostatin-1 （Fer-1）. Myocardial tissue levels of superoxide dismutase （SOD） activity, malondialdehyde （MDA）, reduced glutathione （GSH）, and Fe²⁺ were determined using colorimetric assays. Reactive oxygen species （ROS） levels were assessed by dihydroethidium （DHE） fluorescence staining. The mRNA and protein expression of ferroptosis-related genes （ACSL4, SLC7A11, and GPX4） were measured by RT-qPCR and Western blotting. Myocardial apoptosis was evaluated using TUNEL staining. Mitochondrial ATP content was determined, and ultrastructural changes were observed using transmission electron microscopy （TEM）. Results Compared with the sham group, CKD rats showed decreased body weight, increased heart mass （P < 0.05）, reduced SOD, GSH levels, and significantly elevated MDA, Fe²⁺, and ROS levels （P < 0.05）. ACSL4 expression was markedly upregulated, while SLC7A11 and GPX4 were downregulated （P < 0.05）, accompanied by extensive myocardial apoptosis and decreased ATP content （P < 0.05）. Chronic IS exposure further exacerbated these changes （P < 0.05）, manifesting typical ultrastructural features of ferroptosis, including mitochondrial swelling, cristae rupture, and increased membrane density （P < 0.05）. Fer-1 intervention effectively reversed these alterations, restoring ATP levels, and improving mitochondrial morphology. Conclusion: IS can induce ferroptosis via activation of the mitochondrial pathway, aggravating myocardial oxidative stress and energy metabolism disorders in CKD rats, thereby promoting cardiomyocyte apoptosis. Fer-1 intervention significantly alleviated IS-induced mitochondrial damage and myocardial ferroptosis.
- Uremic toxin,
- Indoxyl sulfate,
- Chronic kidney disease,
- Mitochondrial ferroptosis pathway,
- Myocardial injury,
- Apoptosis

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References(27)

References

[1]	Jankowski J, Floege J, Fliser D, et al. Cardiovascular disease in chronic kidney disease: Pathophysiological insights and therapeutic options[J]. Circulation, 2021, 143(11): 1157-1172. doi: 10.1161/CIRCULATIONAHA.120.050686
[2]	Lim Y J, Sidor N A, Tonial N C, et al. Uremic toxins in the progression of chronic kidney disease and cardiovascular disease: Mechanisms and therapeutic targets[J]. Toxins (Basel), 2021, 13(2): 142. doi: 10.3390/toxins13020142
[3]	Lu P H, Yu M C, Wei M J, et al. The therapeutic strategies for uremic toxins control in chronic kidney disease[J]. Toxins (Basel), 2021, 13(8): 573. doi: 10.3390/toxins13080573
[4]	Karbowska M, Hermanowicz J M, Tankiewicz-Kwedlo A, et al. Neurobehavioral effects of uremic toxin-indoxyl sulfate in the rat model[J]. Sci Rep, 2020, 10(1): 9483.
[5]	Lai Y R, Cheng B C, Lin C N, et al. The effects of indoxyl sulfate and oxidative stress on the severity of peripheral nerve dysfunction in patients with chronic kidney diseases[J]. Antioxidants (Basel), 2022, 11(12): 2350. doi: 10.3390/antiox11122350
[6]	Cui Y, Zhang Y, Zhao X, et al. ACSL4 exacerbates ischemic stroke by promoting ferroptosis-induced brain injury and neuroinflammation[J]. Brain Behav Immun, 2021, 93: 312-321. doi: 10.1016/j.bbi.2021.01.003
[7]	Jiang P, Zhou L, Zhao L, et al. Puerarin attenuates valproate-induced features of ASD in male mice via regulating Slc7a11-dependent ferroptosis[J]. Neuropsychopharmacology, 2024, 49(3): 497-507. doi: 10.1038/s41386-023-01659-4
[8]	Ma T, Du J, Zhang Y, et al. GPX4-independent ferroptosis-a new strategy in disease’s therapy[J]. Cell Death Discov, 2022, 8(1): 434.
[9]	Li W, Xiang Z, Xing Y, et al. Mitochondria bridge HIF signaling and ferroptosis blockage in acute kidney injury[J]. Cell Death Dis, 2022, 13(4): 308. doi: 10.1038/s41419-022-04770-4
[10]	Li H, Ding J, Liu W, et al. Plasma exosomes from patients with acute myocardial infarction alleviate myocardial injury by inhibiting ferroptosis through miR-26b-5p/SLC7A11 axis[J]. Life Sci, 2023, 322: 121649. doi: 10.1016/j.lfs.2023.121649
[11]	Tsai L T, Weng T I, Chang T Y, et al. Inhibition of indoxyl sulfate-induced reactive oxygen species-related ferroptosis alleviates renal cell injury in vitro and chronic kidney disease progression in vivo[J]. Antioxidants (Basel), 2023, 12(11): 1931. doi: 10.3390/antiox12111931
[12]	Adam R J, Williams A C, Kriegel A J. Comparison of the surgical resection and infarct 5/6 nephrectomy rat models of chronic kidney disease[J]. Am J Physiol Renal Physiol, 2022, 322(6): F639-F654. doi: 10.1152/ajprenal.00398.2021
[13]	Karbowska M, Kaminski T W, Znorko B, et al. Indoxyl sulfate promotes arterial thrombosis in rat model via increased levels of complex TF/VII, PAI-1, platelet activation as well as decreased contents of SIRT1 and SIRT3[J]. Front Physiol, 2018, 9: 1623.
[14]	Kuang H, Wang T, Liu L, et al. Treatment of early brain injury after subarachnoid hemorrhage in the rat model by inhibiting p53-induced ferroptosis[J]. Neurosci Lett, 2021, 762: 136134. doi: 10.1016/j.neulet.2021.136134
[15]	Berg A H, Kumar S, Karumanchi S A. Indoxyl sulfate in uremia: An old idea with updated concepts[J]. J Clin Invest, 2022, 132(1): e155860. doi: 10.1172/JCI155860
[16]	Cheng T H, Ma M C, Liao M T, et al. Indoxyl sulfate, a tubular toxin, contributes to the development of chronic kidney disease[J]. Toxins (Basel), 2020, 12(11): E684.
[17]	Takkavatakarn K, Phannajit J, Udomkarnjananun S, et al. Association between indoxyl sulfate and dialysis initiation and cardiac outcomes in chronic kidney disease patients[J]. Int J Nephrol Renovasc Dis, 2022, 15: 115-126. doi: 10.2147/IJNRD.S354658
[18]	Persad K L, Lopaschuk G D. Energy metabolism on mitochondrial maturation and its effects on cardiomyocyte cell fate[J]. Front Cell Dev Biol, 2022, 10: 886393. doi: 10.3389/fcell.2022.886393
[19]	Venditti P, Di Meo S. The role of reactive oxygen species in the life cycle of the mitochondrion[J]. Int J Mol Sci, 2020, 21(6): E2173. doi: 10.3390/ijms21062173
[20]	Sies H. Findings in redox biology: From H₂O₂ to oxidative stress[J]. J Biol Chem, 2020, 295(39): 13458-13473. doi: 10.1074/jbc.X120.015651
[21]	Di Meo S, Venditti P. Evolution of the knowledge of free radicals and other oxidants[J]. Oxid Med Cell Longev, 2020, 2020: 9829176. doi: 10.1155/2020/9829176
[22]	Danieli M G, Antonelli E, Piga M A, et al. Oxidative stress, mitochondrial dysfunction, and respiratory chain enzyme defects in inflammatory myopathies[J]. Autoimmun Rev, 2023, 22(5): 103308.
[23]	Czabotar P E, Garcia-Saez A J. Mechanisms of BCL-2 family proteins in mitochondrial apoptosis[J]. Nat Rev Mol Cell Biol, 2023, 24(10): 732-748. doi: 10.1038/s41580-023-00629-4
[24]	Luo X, O’Neill K L, Huang K. The third model of bax/bak activation: A bcl-2 family feud finally resolved?[J]. F1000Res, 2020, 9: F1000FacultyRev-F1000Faculty935.
[25]	Zhang L, Lu Z, Zhao X. Targeting bcl-2 for cancer therapy[J]. Biochim Biophys Acta Rev Cancer, 2021, 1876(1): 188569. doi: 10.1016/j.bbcan.2021.188569
[26]	Wang J, Liu Y, Wang Y, et al. The cross-link between ferroptosis and kidney diseases[J]. Oxid Med Cell Longev, 2021, 2021: 6654887.
[27]	Zhang X, Li X. Abnormal iron and lipid metabolism mediated ferroptosis in kidney diseases and its therapeutic potential[J]. Metabolites, 2022, 12(1): 58. doi: 10.3390/metabo12010058

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