GCN5L1-mediated TFAM acetylation at K76 participates in mitochondrial biogenesis in acute kidney injury
Abstract Background Mitochondrial dysfunction is an important pathogenic event in acute kidney injury (AKI). GCN5L1 is a specific acetyltransferase in mitochondria, which regulates glucose and fatty acid metabolism. However, the role of GCN5L1 in mitochondrial dysfunction and the pathogenesis of isc...
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BMC
2022-12-01
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Series: | Journal of Translational Medicine |
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Online Access: | https://doi.org/10.1186/s12967-022-03782-0 |
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author | Tingting Lv Yu Zhang XingZhao Ji Shengnan Sun Li Xu Weixia Ma Yi Liu Qiang Wan |
author_facet | Tingting Lv Yu Zhang XingZhao Ji Shengnan Sun Li Xu Weixia Ma Yi Liu Qiang Wan |
author_sort | Tingting Lv |
collection | DOAJ |
description | Abstract Background Mitochondrial dysfunction is an important pathogenic event in acute kidney injury (AKI). GCN5L1 is a specific acetyltransferase in mitochondria, which regulates glucose and fatty acid metabolism. However, the role of GCN5L1 in mitochondrial dysfunction and the pathogenesis of ischemic AKI are not fully understood. Methods The protein level of GCN5L1 was detected by western blot assay. Acetylated proteomics was used to explore the level of acetylated TFAM. Duolink proximity ligation assay and co-immunoprecipitation were used to detect the interaction of TFAM and translocase of outer membrane 70 (TOM70). mtDNA copy number, the expression of mitochondrial electron transport chain complexes, the number and morphology of mitochondria were measured. The renal injury of AKI mice was reflected by the levels of creatinine and urea nitrogen and the pathological changes of renal tissue. Results We showed that GCN5L1 was highly expressed in vivo and in vitro and renal tubules specific knockdown of GCN5L1 could effectively attenuate AKI-induced mitochondrial impairment. Besides, acetylated proteomics revealed that acetylated TFAM was significantly upregulated in AKI mice kidney, which reminded us that TFAM might be an acetylating substrate of GCN5L1. Mechanistically, we evidenced that GCN5L1 could acetylate TFAM at its K76 site and subsequently inhibited its binding to TOM70, thereby reducing TFAM import into mitochondria and mitochondrial biogenesis. Clinically, GCN5L1 and acetylated TFAM were positively correlated with disease severity (all p < 0.05). Conclusions In sum, these data demonstrated an unrecognized regulating mechanism of GCN5L1 on TFAM acetylation and its intracellular trafficking, and a potential intervening target for AKI associated mitochondrial disorders as well. |
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last_indexed | 2024-04-11T14:15:21Z |
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spelling | doaj.art-0e7c3a35a8934b21afc418e3fa8142932022-12-22T04:19:26ZengBMCJournal of Translational Medicine1479-58762022-12-0120111510.1186/s12967-022-03782-0GCN5L1-mediated TFAM acetylation at K76 participates in mitochondrial biogenesis in acute kidney injuryTingting Lv0Yu Zhang1XingZhao Ji2Shengnan Sun3Li Xu4Weixia Ma5Yi Liu6Qiang Wan7Department of Cancer Center, Shandong Provincial Hospital Affiliated to Shandong First Medical UniversityDepartment of Allergy, Department of Pulmonary and Critical Care Medicine, Shandong Provincial Hospital, Shandong UniversityDepartment of Allergy, Department of Pulmonary and Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical UniversityCenter of Cell Metabolism and Disease, Jinan Central Hospital, Shandong UniversityDepartment of Allergy, Department of Pulmonary and Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical UniversityDepartment of Allergy, Department of Pulmonary and Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical UniversityDepartment of Allergy, Department of Pulmonary and Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical UniversityCenter of Cell Metabolism and Disease, Jinan Central Hospital, Shandong UniversityAbstract Background Mitochondrial dysfunction is an important pathogenic event in acute kidney injury (AKI). GCN5L1 is a specific acetyltransferase in mitochondria, which regulates glucose and fatty acid metabolism. However, the role of GCN5L1 in mitochondrial dysfunction and the pathogenesis of ischemic AKI are not fully understood. Methods The protein level of GCN5L1 was detected by western blot assay. Acetylated proteomics was used to explore the level of acetylated TFAM. Duolink proximity ligation assay and co-immunoprecipitation were used to detect the interaction of TFAM and translocase of outer membrane 70 (TOM70). mtDNA copy number, the expression of mitochondrial electron transport chain complexes, the number and morphology of mitochondria were measured. The renal injury of AKI mice was reflected by the levels of creatinine and urea nitrogen and the pathological changes of renal tissue. Results We showed that GCN5L1 was highly expressed in vivo and in vitro and renal tubules specific knockdown of GCN5L1 could effectively attenuate AKI-induced mitochondrial impairment. Besides, acetylated proteomics revealed that acetylated TFAM was significantly upregulated in AKI mice kidney, which reminded us that TFAM might be an acetylating substrate of GCN5L1. Mechanistically, we evidenced that GCN5L1 could acetylate TFAM at its K76 site and subsequently inhibited its binding to TOM70, thereby reducing TFAM import into mitochondria and mitochondrial biogenesis. Clinically, GCN5L1 and acetylated TFAM were positively correlated with disease severity (all p < 0.05). Conclusions In sum, these data demonstrated an unrecognized regulating mechanism of GCN5L1 on TFAM acetylation and its intracellular trafficking, and a potential intervening target for AKI associated mitochondrial disorders as well.https://doi.org/10.1186/s12967-022-03782-0GCN5L1AcetylationTFAMMitochondrial biogenesisAcute kidney injury |
spellingShingle | Tingting Lv Yu Zhang XingZhao Ji Shengnan Sun Li Xu Weixia Ma Yi Liu Qiang Wan GCN5L1-mediated TFAM acetylation at K76 participates in mitochondrial biogenesis in acute kidney injury Journal of Translational Medicine GCN5L1 Acetylation TFAM Mitochondrial biogenesis Acute kidney injury |
title | GCN5L1-mediated TFAM acetylation at K76 participates in mitochondrial biogenesis in acute kidney injury |
title_full | GCN5L1-mediated TFAM acetylation at K76 participates in mitochondrial biogenesis in acute kidney injury |
title_fullStr | GCN5L1-mediated TFAM acetylation at K76 participates in mitochondrial biogenesis in acute kidney injury |
title_full_unstemmed | GCN5L1-mediated TFAM acetylation at K76 participates in mitochondrial biogenesis in acute kidney injury |
title_short | GCN5L1-mediated TFAM acetylation at K76 participates in mitochondrial biogenesis in acute kidney injury |
title_sort | gcn5l1 mediated tfam acetylation at k76 participates in mitochondrial biogenesis in acute kidney injury |
topic | GCN5L1 Acetylation TFAM Mitochondrial biogenesis Acute kidney injury |
url | https://doi.org/10.1186/s12967-022-03782-0 |
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