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 dys- regulates Akt-GSK3β complex in response to insulin, hindering the accumulation of pGSK3βS9 into the mito- chondria. 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 mito- chondria. 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.

Document Type

Article

Publication Date

2024

Notes/Citation Information

2213-2317/© 2024 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Digital Object Identifier (DOI)

https://doi.org/10.1016/j.redox.2024.103221

Funding Information

This work has been supported by Fondi Ateneo grants funded by Sapienza University (#RM120172A3160B53 and #RG11916B 87F55459) to EB; by the Alzheimer’s Association grant (#2019-AARG- 643091) to EB; by Banca d’Italia funded grant (#1130944/22) to EB; by the Swedish Research Council (#2019-01130) and the Albert Påhlssons stiftelse to JMND. JMND acknowledges support from The Knut and Alice Wallenberg foundation and the Lund University Diabetes Centre, which is funded by the Swedish Research Council (EXODIAB 2009-1039) and the Swedish Foundation for Strategic Research (IRC15-0067).

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