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Abstract: SA-PO501

Lysyl Oxidase-Like 4 Acts as a Deacetylase to Regulate Mitochondrial Respiration in Diabetic Kidney Tubule

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Ke, Qingqing, Nanjing Medical University, Nanjing, China
  • Zhou, Yang, Second Affiliated Hospital, Nanjing Medical University, Nanjing, JIangSu, China
  • Yang, Junwei, Second Affiliated Hospital, Nanjing Medical University, Nanjing, JIangSu, China
Background

Dysfunctions in mitochondrial respiration and energy production are quite evident in the pathogenesis of diabetic kidney disease; however, the underlying mechanism remains unclear. Acetylation negatively regulates the activity of enzymes involved in the process of mitochondrial respiration. With the N-terminal scavenger receptor cysteine-rich (SRCR) repeats, lysyl oxidase-like 4 (LOXL4) may act as a deacetylase. In the present study, we aimed to investigate whether the LOXL4 regulates enzyme acetylation and mitochondrial respiration of renal tubular cells in diabetes.

Methods

Kidney biopsy samples were obtained from patients without or with diabetes. Protein acetylation was determined by mass spectrometry of isolated kidney tubule from control and STZ-induce diabetic mice. Mitochondrial respiration was measured by oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). Protein expression and localization of LOXL4 were examined by western blot and immunofluorescence staining. Expression of LOXL4 was modulated by plasmid or siRNA in primary cultured tubular epithelial cells to determine the effect of LOXL4 on acetylation.

Results

In kidney tubule of diabetic mice, the acetylation was upregulated and downregulated in 588 and 105 proteins, respectively. Besides cyroplasm, abundant of these acetylated/deacetylated proteins locate in mitochondria. Bioinformatics analysis suggested that these proteins are evolved in mitochondrial respiration and probably regulate metabolic process and energy production. Consistently, mitochondrial respiration capacity was impaired in tubular cells treated with high glucose. The expression of LOXL4 was markedly increased in kidney tubule of both diabetic patients and mouse model. Moreover, immune staining showed the colocalization of LOXL4 and mitochondria. Modulation of the expression of LOXL4 regulated the acetylation of mitochondrial proteins and affected mitochondrial respiration and energy production.

Conclusion

Collectively, lysyl oxidase-like 4 may regulate the acetylation/deacetylation of mitochondrial proteins and protects mitochondrial respiration and function in diabetic kidney tubule.

Funding

  • Government Support - Non-U.S.