TY - JOUR
T1 - Biliverdin Reductase-A integrates insulin signaling with mitochondrial metabolism through phosphorylation of GSK3β
AU - Lanzillotta, Chiara
AU - Tramutola, Antonella
AU - Lanzillotta, Simona
AU - Greco, Viviana
AU - Pagnotta, Sara
AU - Sanchini, Caterina
AU - Di Angelantonio, Silvia
AU - Forte, Elena
AU - Rinaldo, Serena
AU - Paone, Alessio
AU - Cutruzzolà, Francesca
AU - Cimini, Flavia Agata
AU - Barchetta, Ilaria
AU - Cavallo, Maria Gisella
AU - Urbani, Andrea
AU - Butterfield, D. Allan
AU - Di Domenico, Fabio
AU - Paul, Bindu D.
AU - Perluigi, Marzia
AU - Duarte, Joao M.N.
AU - Barone, Eugenio
N1 - Publisher Copyright:
© 2024 The Authors
PY - 2024/7
Y1 - 2024/7
N2 - 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.
AB - 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.
KW - Biliverdin reductase-A
KW - Brain insulin resistance
KW - GSK3β
KW - Mitochondrial metabolism
KW - Mitochondrial unfolded protein response
KW - Oxidative stress
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UR - http://www.scopus.com/inward/citedby.url?scp=85195097821&partnerID=8YFLogxK
U2 - 10.1016/j.redox.2024.103221
DO - 10.1016/j.redox.2024.103221
M3 - Article
C2 - 38843768
AN - SCOPUS:85195097821
SN - 2213-2317
VL - 73
JO - Redox Biology
JF - Redox Biology
M1 - 103221
ER -
