Biliverdin Reductase-A integrates insulin signaling with mitochondrial metabolism through phosphorylation of GSK3β
Chiara Lanzillotta,
Antonella Tramutola,
Simona Lanzillotta,
Viviana Greco,
Sara Pagnotta,
Caterina Sanchini,
Silvia Di Angelantonio,
Elena Forte,
Serena Rinaldo,
Alessio Paone,
Francesca Cutruzzolà,
Flavia Agata Cimini,
Ilaria Barchetta,
Maria Gisella Cavallo,
Andrea Urbani,
D. Allan Butterfield,
Fabio Di Domenico,
Bindu D. Paul,
Marzia Perluigi,
Joao M.N. Duarte,
Eugenio Barone
Affiliations
Chiara Lanzillotta
Department of Biochemical Sciences “A. Rossi-Fanelli”, Sapienza University of Rome, Italy
Antonella Tramutola
Department of Biochemical Sciences “A. Rossi-Fanelli”, Sapienza University of Rome, Italy
Simona Lanzillotta
Department of Biochemical Sciences “A. Rossi-Fanelli”, Sapienza University of Rome, Italy
Viviana Greco
Department of Basic Biotechnology, Perioperative and Intensive Clinics, Faculty of Medicine and Surgery, Catholic University of the Sacred Heart, L.go F.Vito 1, 00168, Rome, Italy; Fondazione Policlinico Universitario A. Gemelli IRCCS, L.go A.Gemelli 8, 00168, Rome, Italy
Sara Pagnotta
Department of Biochemical Sciences “A. Rossi-Fanelli”, Sapienza University of Rome, Italy
Caterina Sanchini
Center for Life Nano- & Neuro-Science, Istituto Italiano di Tecnologia, 00161, Rome, Italy
Silvia Di Angelantonio
Center for Life Nano- & Neuro-Science, Istituto Italiano di Tecnologia, 00161, Rome, Italy; Department of Physiology and Pharmacology, Sapienza University of Rome, Italy
Elena Forte
Department of Biochemical Sciences “A. Rossi-Fanelli”, Sapienza University of Rome, Italy
Serena Rinaldo
Department of Biochemical Sciences “A. Rossi-Fanelli”, Sapienza University of Rome, Italy
Alessio Paone
Department of Biochemical Sciences “A. Rossi-Fanelli”, Sapienza University of Rome, Italy
Francesca Cutruzzolà
Department of Biochemical Sciences “A. Rossi-Fanelli”, Sapienza University of Rome, Italy
Flavia Agata Cimini
Department of Experimental Medicine, Sapienza University of Rome, Italy
Ilaria Barchetta
Department of Experimental Medicine, Sapienza University of Rome, Italy
Maria Gisella Cavallo
Department of Experimental Medicine, Sapienza University of Rome, Italy
Andrea Urbani
Department of Basic Biotechnology, Perioperative and Intensive Clinics, Faculty of Medicine and Surgery, Catholic University of the Sacred Heart, L.go F.Vito 1, 00168, Rome, Italy; Fondazione Policlinico Universitario A. Gemelli IRCCS, L.go A.Gemelli 8, 00168, Rome, Italy
D. Allan Butterfield
Sanders-Brown Center on Aging, Department of Chemistry, University of Kentucky, Lexington, KY, USA
Fabio Di Domenico
Department of Biochemical Sciences “A. Rossi-Fanelli”, Sapienza University of Rome, Italy
Bindu D. Paul
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Lieber Institute for Brain Development, Baltimore, MD, USA
Marzia Perluigi
Department of Biochemical Sciences “A. Rossi-Fanelli”, Sapienza University of Rome, Italy
Joao M.N. Duarte
Department of Experimental Medical Science, Faculty of Medicine, Lund University, Sweden; Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden
Eugenio Barone
Department of Biochemical Sciences “A. Rossi-Fanelli”, Sapienza University of Rome, Italy; Corresponding author.
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.
