Abstract: SA-OR119

SGLT2 Inhibitors Induce Local Mitochondrial Unfolded Protein Responses in the Proximal Tubules by Suppressing Mitoribosome Proliferation and Influencing Mitonuclear Imbalance in Diabetic Nephropathy

Session Information

Category: Diabetes

  • 501 Diabetes Mellitus and Obesity: Basic - Experimental

Authors

  • Umino, Hiroyuki, Keio University School of Medicine, Tokyo, Japan
  • Hasegawa, Kazuhiro, Keio University School of Medicine, Tokyo, Japan
  • Wakino, Shu, Keio University School of Medicine, Tokyo, Japan
  • Itoh, Hiroshi, Keio University School of Medicine, Tokyo, Japan
Background

We have previously reported a molecular mechanism by which SGLT2 inhibitors maintain the anti-aging gene SIRT1. The findings that mitoribosome blockage causes mitonuclear imbalance and induces mitochondrial unfolded protein responses (UPRs) are reportedly linked to longevity. These changes also underlie the elongation occurring from modulation of NAD metabolism and SIRT1. In this study, we analyzed whether SGLT2 inhibition and SIRT1 retention would produce this effect in the proximal tubules.

Methods

Canagliflozin (Cana), a SGLT2 inhibitor, was administered to 8-week-old db/m and db/db mice, and the following parameters were evaluated at 16 weeks of age: (1) SGLT2 and SIRT1 expression; (2) mitoribosome and cytoplasmic ribosome (cytoribosome) numbers on electron microscopy; and (3) COX1, representing mitoribosome function, which is encoded by mitochondrial DNA and translated in mitoribosomes, and ATP5A, a marker protein reflecting cytoribosome function, which is encoded by nuclear DNA and translated in cytoribosomes.

Results

In db/db mice, SGLT2 expression was elevated and SIRT1 expression was decreased; these changes were suppressed in db/db mice treated with Cana. In db/db mice, an elevated mitoribosomal number was observed despite no marked change in the cytoribosomal number in the proximal tubules observed on electron microscopy. Consistent with mitoribosomal proliferation, a significant increase in COX1 was detected in db/db, whereas ATP5A was not changed. The elevation in mitoribosomal number and function was suppressed in db/db + Cana. Such specific inhibition of mitoribosome protein expression can lead to mitonuclear protein imbalance and associated UPRmt. One of the marker proteins induced by UPRmt is heat shock protein 60 (HSP60). Indeed, elevation of HSP60 was detected in db/db + Cana.

Conclusion

A mitoribosome synthesizes the enzyme complexes of the electron transport system in the inner membrane (Complexes I–IV). Its increase suggests excessive ATP and ROS production and is a sign of metabolic regulation failure. However, a SGLT2 inhibitor induces an apt stress response caused by UPRmt. This newly identified organelle change occurs in early-stage diabetic nephropathy, and the mitoribosome may serve as a novel therapeutic target.