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

被引：9

作者：

Lanzillotta, Chiara ^{[1
]}

Tramutola, Antonella ^{[1
]}

Lanzillotta, Simona ^{[1
]}

Greco, Viviana ^{[2
,3
]}

Pagnotta, Sara ^{[1
]}

Sanchini, Caterina ^{[4
]}

Di Angelantonio, Silvia ^{[4
,5
]}

Forte, Elena ^{[1
]}

Rinaldo, Serena ^{[1
]}

Paone, Alessio ^{[1
]}

Cutruzzola, Francesca ^{[1
]}

Cimini, Flavia Agata ^{[6
]}

Barchetta, Ilaria ^{[6
]}

Cavallo, Maria Gisella ^{[6
]}

Urbani, Andrea ^{[2
,3
]}

Butterfield, D. Allan ^{[7
]}

Di Domenico, Fabio ^{[1
]}

Paul, Bindu D. ^{[8
,9
,10
,11
]}

Perluigi, Marzia ^{[1
]}

Duarte, Joao M. N. ^{[12
,13
]}

Barone, Eugenio ^{[1
]}

机构：

[1] Sapienza Univ Rome, Dept Biochem Sci A Rossi Fanelli, Rome, Italy

[2] Univ Cattolica Sacro Cuore, Fac Med & Surg, Dept Basic Biotechnol Perioperat & Intens Clin, Lgo F Vito 1, I-00168 Rome, Italy

[3] Fdn Policlin Univ A Gemelli IRCCS, Lgo A Gemelli 8, I-00168 Rome, Italy

[4] Ist Italiano Tecnol, Ctr Life Nano & Neurosci, I-00161 Rome, Italy

[5] Sapienza Univ Rome, Dept Physiol & Pharmacol, Rome, Italy

[6] Sapienza Univ Rome, Dept Expt Med, Rome, Italy

[7] Univ Kentucky, Sanders Brown Ctr Aging, Dept Chem, Lexington, KY USA

[8] Johns Hopkins Univ, Sch Med, Solomon H Snyder Dept Neurosci, Baltimore, MD USA

[9] Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD USA

[10] Johns Hopkins Univ, Dept Psychiat & Behav Sci, Sch Med, Baltimore, MD USA

[11] Lieber Inst Brain Dev, Baltimore, MD USA

[12] Lund Univ, Fac Med, Dept Expt Med Sci, Lund, Sweden

[13] Lund Univ, Wallenberg Ctr Mol Med, Lund, Sweden

来源：

REDOX BIOLOGY | 2024年 / 73卷

基金：

瑞典研究理事会;

关键词：

Biliverdin reductase-A; Brain insulin resistance; GSK3; beta; Mitochondrial metabolism; Mitochondrial unfolded protein response; Oxidative stress; COGNITIVE IMPAIRMENT; INTRANASAL INSULIN; ALZHEIMERS-DISEASE; OXIDATIVE STRESS; BRAIN; MEMORY; RESISTANCE; GLUCOSE; MECHANISM; ANXIETY;

D O I：

10.1016/j.redox.2024.103221

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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-GSK3 beta complex in response to insulin, hindering the accumulation of pGSK3 beta S9 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 pGSK3 beta S9 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.

引用

页数：24

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