Brain insulin signaling acts as a key regulator for gene expression and cellular metabolism, both events sustaining neuronal activity and synaptic plasticity mechanisms. Alterations of this pathway, known as brain insulin resistance, are associated with a higher risk to develop age-related cognitive decline and neurodegeneration.Among the molecular mechanisms identified to promote brain insulin resistance, mitochondrial dysfunctions, failure of energy metabolism, and increased oxidative stress levels have been found to play a role. Studies from our group uncovered the role of the enzyme biliverdin reductase A (BVRA) that, beyond its activity in the degradation pathway of heme, is a novel regulator of the insulin signaling. BVRA regulates insulin signaling pathway by working either as a S/T/Y kinase or a scaffold protein. In particular, BVRA is required to promote the AKT-mediated inhibition of GSK3β in response to insulin, that promotes cell metabolism and survival. Findings from our group revealed that a reduction of BVRA protein levels is a key event driving brain insulin resistance development. Moreover, we identified a novel mechanism for which loss of BVRA is responsible for GSK3β hyper-activation that drives mitochondrial stress and bioenergetics failure in response to insulin in neuronal cells. These alterations accelerate the impairment of energy metabolism and the development of neurodegeneration. Conversely, rescuing BVRA functions reduces oxidative stress levels, ameliorates brain insulin signaling activation and cellular metabolism, finally contributing to improved cognitive functions in animal models of neurodegeneration. Overall, our data suggest that BVRA links insulin signaling activation and mitochondrial bioenergetics to preserve cellular homeostasis and preventing the development of neurodegeneration.
March 23, 2023
Prof. Eugenio Barone
Department of Biochemical Sciences
Sapienza University of Rome
eugenio.barone@uniroma1.it
Time: 1:00 pm
Place: Aula C, CU010