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. 2024 Apr;240(4):e14121.
doi: 10.1111/apha.14121. Epub 2024 Feb 26.

Mitochondrial fumarate promotes ischemia/reperfusion-induced tubular injury

Zuo-Lin Li  1 , Ming-Min Huang  1 , Meng-Yao Yu  1 , Di-Fei Nie  1 , Sha-Li Fu  1 , Jing-Jing Di  1 , Ting Lan  1 , Bi-Cheng Liu  1 , Qiu-Li Wu  1
Affiliations

Mitochondrial fumarate promotes ischemia/reperfusion-induced tubular injury

Zuo-Lin Li et al. Acta Physiol (Oxf). 2024 Apr.

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.

Keywords: fumarate; glutathione; ischemia/reperfusion; mitochondria; tubule injury.

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References

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