Brain insulin resistance links the failure of energy metabolism with cognitive decline in both type 2 Diabetes Mellitus (T2D) and Alzheimer's disease (AD), although the molecular changes preceding overt brain insulin resistance remain unexplored. Abnormal biliverdin reductase-A (BVR-A) levels were observed in both T2D and AD and were associated with insulin resistance. Here, we demonstrate that reduced BVR-A levels alter insulin signaling and mitochondrial bioenergetics in the brain. Loss of BVR-A leads to IRS1 hyper-activation but dysregulates Akt-GSK3β complex in response to insulin, hindering the accumulation of pGSK3βS9 into the mitochondria. This event impairs oxidative phosphorylation and fosters the activation of the mitochondrial Unfolded Protein Response (UPRmt). Remarkably, we unveil that BVR-A is required to shuttle pGSK3βS9 into the mitochondria. Our data sheds light on the intricate interplay between insulin signaling and mitochondrial metabolism in the brain unraveling potential targets for mitigating the development of brain insulin resistance and neurodegeneration.

Biliverdin reductase-A integrates insulin signaling with mitochondrial metabolism through phosphorylation of GSK3β / Lanzillotta, Chiara; Tramutola, Antonella; Lanzillotta, Simona; Greco, Viviana; Pagnotta, Sara; Sanchini, Caterina; Di Angelantonio, Silvia; Forte, Elena; Rinaldo, Serena; Paone, Alessio; Cutruzzolà, Francesca; Cimini, Flavia Agata; Barchetta, Ilaria; Cavallo, Maria Gisella; Urbani, Andrea; Butterfield, D Allan; Di Domenico, Fabio; Paul, Bindu D; Perluigi, Marzia; Duarte, Joao M N; Barone, Eugenio. - In: REDOX BIOLOGY. - ISSN 2213-2317. - 73:(2024). [10.1016/j.redox.2024.103221]

Biliverdin reductase-A integrates insulin signaling with mitochondrial metabolism through phosphorylation of GSK3β

Lanzillotta, Chiara;Tramutola, Antonella;Lanzillotta, Simona;Pagnotta, Sara;Sanchini, Caterina;Di Angelantonio, Silvia;Forte, Elena;Rinaldo, Serena;Paone, Alessio;Cimini, Flavia Agata;Barchetta, Ilaria;Cavallo, Maria Gisella;Di Domenico, Fabio;Perluigi, Marzia;Barone, Eugenio
2024

Abstract

Brain insulin resistance links the failure of energy metabolism with cognitive decline in both type 2 Diabetes Mellitus (T2D) and Alzheimer's disease (AD), although the molecular changes preceding overt brain insulin resistance remain unexplored. Abnormal biliverdin reductase-A (BVR-A) levels were observed in both T2D and AD and were associated with insulin resistance. Here, we demonstrate that reduced BVR-A levels alter insulin signaling and mitochondrial bioenergetics in the brain. Loss of BVR-A leads to IRS1 hyper-activation but dysregulates Akt-GSK3β complex in response to insulin, hindering the accumulation of pGSK3βS9 into the mitochondria. This event impairs oxidative phosphorylation and fosters the activation of the mitochondrial Unfolded Protein Response (UPRmt). Remarkably, we unveil that BVR-A is required to shuttle pGSK3βS9 into the mitochondria. Our data sheds light on the intricate interplay between insulin signaling and mitochondrial metabolism in the brain unraveling potential targets for mitigating the development of brain insulin resistance and neurodegeneration.
2024
Biliverdin reductase-A; brain insulin resistance; GSK3β; mitochondrial metabolism; mitochondrial unfolded protein response; oxidative stress
01 Pubblicazione su rivista::01a Articolo in rivista
Biliverdin reductase-A integrates insulin signaling with mitochondrial metabolism through phosphorylation of GSK3β / Lanzillotta, Chiara; Tramutola, Antonella; Lanzillotta, Simona; Greco, Viviana; Pagnotta, Sara; Sanchini, Caterina; Di Angelantonio, Silvia; Forte, Elena; Rinaldo, Serena; Paone, Alessio; Cutruzzolà, Francesca; Cimini, Flavia Agata; Barchetta, Ilaria; Cavallo, Maria Gisella; Urbani, Andrea; Butterfield, D Allan; Di Domenico, Fabio; Paul, Bindu D; Perluigi, Marzia; Duarte, Joao M N; Barone, Eugenio. - In: REDOX BIOLOGY. - ISSN 2213-2317. - 73:(2024). [10.1016/j.redox.2024.103221]
File allegati a questo prodotto
File Dimensione Formato  
Lanzillotta_Biliverdin_2024.pdf

accesso aperto

Tipologia: Versione editoriale (versione pubblicata con il layout dell'editore)
Licenza: Creative commons
Dimensione 1.75 MB
Formato Adobe PDF
1.75 MB Adobe PDF

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1711799
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 0
  • ???jsp.display-item.citation.isi??? ND
social impact