Renalase inhibition regulates β cell metabolism to defend against acute and chronic stress

MacDonald, T. L.; Ryback, B.; Aparecida da Silva Pereira, J.; Wei, S.; Mendez, B.; Cai, E.; Ishikawa, Y.; Weir, G.; Bonner-Weir, S.; Kissler, S.; Yi, P.

doi:10.1101/2024.06.11.598322

bioRxiv · 10.1101/2024.06.11.598322

Renalase inhibition regulates β cell metabolism to defend against acute and chronic stress

MacDonald, T. L.·Ryback, B.·Aparecida da Silva Pereira, J.·Wei, S.·Mendez, B.·Cai, E.·Ishikawa, Y.·Weir, G.·Bonner-Weir, S.·Kissler, S.·Yi, P.

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Abstract

Renalase (Rnls), annotated as an oxidase enzyme, is a GWAS gene associated with Type 1 Diabetes (T1D) risk. We previously discovered that Rnls inhibition delays diabetes onset in mouse models of T1D in vivo, and protects pancreatic {beta} cells against autoimmune killing, ER and oxidative stress in vitro. The molecular biochemistry and functions of Rnls are entirely uncharted. Here we find that Rnls inhibition defends against loss of {beta} cell mass and islet dysfunction in chronically stressed Akita mice in vivo. We used RNA sequencing, untargeted and targeted metabolomics and metabolic function experiments in mouse and human {beta} cells and discovered a robust and conserved metabolic shift towards glycolysis, amino acid abundance and GSH synthesis to counter protein misfolding stress, in vitro. Our work illustrates a function for Rnls in mammalian cells, and suggests an axis by which manipulating intrinsic properties of {beta} cells can rewire metabolism to protect against diabetogenic stress.

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MacDonald, T. L., Ryback, B., Aparecida da Silva Pereira, J., Wei, S., Mendez, B., Cai, E., Ishikawa, Y., Weir, G., Bonner-Weir, S., Kissler, S., Yi, P.. 2024-06-13. Renalase inhibition regulates β cell metabolism to defend against acute and chronic stress. https://doi.org/10.1101/2024.06.11.598322

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