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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 and Paone, Alessio , et al. (2024) In Redox Biology 73.
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... (More)

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.

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type
Contribution to journal
publication status
published
subject
keywords
Biliverdin reductase-A, Brain insulin resistance, GSK3β, Mitochondrial metabolism, Mitochondrial unfolded protein response, Oxidative stress
in
Redox Biology
volume
73
article number
103221
publisher
Elsevier
external identifiers
  • pmid:38843768
  • scopus:85195097821
ISSN
2213-2317
DOI
10.1016/j.redox.2024.103221
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2024 The Authors
id
991ab405-d20b-472e-bb34-bd2d7db0508c
date added to LUP
2024-11-06 14:33:40
date last changed
2025-04-24 05:46:32
@article{991ab405-d20b-472e-bb34-bd2d7db0508c,
  abstract     = {{<p>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 pGSK3β<sup>S9</sup> 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 pGSK3β<sup>S9</sup> 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.</p>}},
  author       = {{Lanzillotta, Chiara and Tramutola, Antonella and Lanzillotta, Simona and Greco, Viviana and Pagnotta, Sara and Sanchini, Caterina and Di Angelantonio, Silvia and Forte, Elena and Rinaldo, Serena and Paone, Alessio and Cutruzzolà, Francesca and Cimini, Flavia Agata and Barchetta, Ilaria and Cavallo, Maria Gisella and Urbani, Andrea and Butterfield, D. Allan and Di Domenico, Fabio and Paul, Bindu D. and Perluigi, Marzia and Duarte, Joao M.N. and Barone, Eugenio}},
  issn         = {{2213-2317}},
  keywords     = {{Biliverdin reductase-A; Brain insulin resistance; GSK3β; Mitochondrial metabolism; Mitochondrial unfolded protein response; Oxidative stress}},
  language     = {{eng}},
  publisher    = {{Elsevier}},
  series       = {{Redox Biology}},
  title        = {{Biliverdin Reductase-A integrates insulin signaling with mitochondrial metabolism through phosphorylation of GSK3β}},
  url          = {{http://dx.doi.org/10.1016/j.redox.2024.103221}},
  doi          = {{10.1016/j.redox.2024.103221}},
  volume       = {{73}},
  year         = {{2024}},
}