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Mitochondrial fumarate promotes ischemia/reperfusion‐induced tubular injury.

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Title: Mitochondrial fumarate promotes ischemia/reperfusion‐induced tubular injury.
Authors: Li, Zuo‐Lin (AUTHOR), Huang, Ming‐Min (AUTHOR), Yu, Meng‐Yao (AUTHOR), Nie, Di‐Fei (AUTHOR), Fu, Sha‐Li (AUTHOR), Di, Jing‐Jing (AUTHOR), Lan, Ting (AUTHOR), Liu, Bi‐Cheng (AUTHOR), Wu, Qiu‐Li (AUTHOR)
Source: Acta Physiologica. Apr2024, Vol. 240 Issue 4, p1-17. 17p.
Subjects: Mitochondria, Reactive oxygen species, Transmission electron microscopy, Wounds & injuries, Reperfusion injury
Abstract: Aim: Mitochondrial dysfunction, a characteristic pathological feature of renal Ischemic/reperfusion injury (I/RI), predisposes tubular epithelial cells to maintain an inflammatory microenvironment, however, the exact mechanisms through which mitochondrial dysfunction modulates the induction of tubular injury remains incompletely understood. Methods: ESI‐QTRAP‐MS/MS approach was used to characterize the targeted metabolic profiling of kidney with I/RI. Tubule injury, mitochondrial dysfunction, and fumarate level were evaluated using qPCR, transmission electron microscopy, ELISA, and immunohistochemistry. Results: We demonstrated that tubule injury occurred at the phase of reperfusion in murine model of I/RI. Meanwhile, enhanced glycolysis and mitochondrial dysfunction were found to be associated with tubule injury. Further, we found that tubular fumarate, which resulted from fumarate hydratase deficiency and released from dysfunctional mitochondria, promoted tubular injury. Mechanistically, fumarate induced tubular injury by causing disturbance of glutathione (GSH) hemostasis. Suppression of GSH with buthionine sulphoximine administration could deteriorate the fumarate inhibition‐mediated tubule injury recovery. Reactive oxygen species/NF‐κB signaling activation played a vital role in fumarate‐mediated tubule injury. Conclusion: Our studies demonstrated that the mitochondrial‐derived fumarate promotes tubular epithelial cell injury in renal I/RI. Blockade of fumarate‐mediated ROS/NF‐κB signaling activation may serve as a novel therapeutic approach to ameliorate hypoxic tubule injury. [ABSTRACT FROM AUTHOR]
Copyright of Acta Physiologica is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Psychology and Behavioral Sciences Collection
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  Data: Mitochondrial fumarate promotes ischemia/reperfusion‐induced tubular injury.
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  Data: <searchLink fieldCode="AR" term="%22Li%2C+Zuo‐Lin%22">Li, Zuo‐Lin</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Huang%2C+Ming‐Min%22">Huang, Ming‐Min</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Yu%2C+Meng‐Yao%22">Yu, Meng‐Yao</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Nie%2C+Di‐Fei%22">Nie, Di‐Fei</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Fu%2C+Sha‐Li%22">Fu, Sha‐Li</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Di%2C+Jing‐Jing%22">Di, Jing‐Jing</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Lan%2C+Ting%22">Lan, Ting</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Liu%2C+Bi‐Cheng%22">Liu, Bi‐Cheng</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Wu%2C+Qiu‐Li%22">Wu, Qiu‐Li</searchLink> (AUTHOR)
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  Data: <searchLink fieldCode="JN" term="%22Acta+Physiologica%22">Acta Physiologica</searchLink>. Apr2024, Vol. 240 Issue 4, p1-17. 17p.
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  Data: <searchLink fieldCode="DE" term="%22Mitochondria%22">Mitochondria</searchLink><br /><searchLink fieldCode="DE" term="%22Reactive+oxygen+species%22">Reactive oxygen species</searchLink><br /><searchLink fieldCode="DE" term="%22Transmission+electron+microscopy%22">Transmission electron microscopy</searchLink><br /><searchLink fieldCode="DE" term="%22Wounds+%26+injuries%22">Wounds & injuries</searchLink><br /><searchLink fieldCode="DE" term="%22Reperfusion+injury%22">Reperfusion injury</searchLink>
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  Label: Abstract
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  Data: Aim: Mitochondrial dysfunction, a characteristic pathological feature of renal Ischemic/reperfusion injury (I/RI), predisposes tubular epithelial cells to maintain an inflammatory microenvironment, however, the exact mechanisms through which mitochondrial dysfunction modulates the induction of tubular injury remains incompletely understood. Methods: ESI‐QTRAP‐MS/MS approach was used to characterize the targeted metabolic profiling of kidney with I/RI. Tubule injury, mitochondrial dysfunction, and fumarate level were evaluated using qPCR, transmission electron microscopy, ELISA, and immunohistochemistry. Results: We demonstrated that tubule injury occurred at the phase of reperfusion in murine model of I/RI. Meanwhile, enhanced glycolysis and mitochondrial dysfunction were found to be associated with tubule injury. Further, we found that tubular fumarate, which resulted from fumarate hydratase deficiency and released from dysfunctional mitochondria, promoted tubular injury. Mechanistically, fumarate induced tubular injury by causing disturbance of glutathione (GSH) hemostasis. Suppression of GSH with buthionine sulphoximine administration could deteriorate the fumarate inhibition‐mediated tubule injury recovery. Reactive oxygen species/NF‐κB signaling activation played a vital role in fumarate‐mediated tubule injury. Conclusion: Our studies demonstrated that the mitochondrial‐derived fumarate promotes tubular epithelial cell injury in renal I/RI. Blockade of fumarate‐mediated ROS/NF‐κB signaling activation may serve as a novel therapeutic approach to ameliorate hypoxic tubule injury. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
  Group: Ab
  Data: <i>Copyright of Acta Physiologica is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1111/apha.14121
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        Text: English
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      – SubjectFull: Transmission electron microscopy
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      – SubjectFull: Wounds & injuries
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      – SubjectFull: Reperfusion injury
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      – TitleFull: Mitochondrial fumarate promotes ischemia/reperfusion‐induced tubular injury.
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              M: 04
              Text: Apr2024
              Type: published
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