IGF1R Deficiency Modulates Brain Signaling Pathways and Disturbs Mitochondria and Redox Homeostasis

Abstract

Insulin-like growth factor 1 receptor (IGF1R)-mediated signaling pathways modulate important neurophysiological aspects in the central nervous system, including neurogenesis, synaptic plasticity and complex cognitive functions. In the present study, we intended to characterize the impact of IGF1R deficiency in the brain, focusing on PI3K/Akt and MAPK/ERK1/2 signaling pathways and mitochondria-related parameters. For this purpose, we used 13-week-old UBC-CreERT2; Igf1rfl/fl male mice in which Igf1r was conditionally deleted. IGF1R deficiency caused a decrease in brain weight as well as the activation of the IR/PI3K/Akt and inhibition of the MAPK/ERK1/2/CREB signaling pathways. Despite no alterations in the activity of caspases 3 and 9, a significant alteration in phosphorylated GSK3β and an increase in phosphorylated Tau protein levels were observed. In addition, significant disturbances in mitochondrial dynamics and content and altered activity of the mitochondrial respiratory chain complexes were noticed. An increase in oxidative stress, characterized by decreased nuclear factor E2-related factor 2 (NRF2) protein levels and aconitase activity and increased H2O2 levels were also found in the brain of IGF1R-deficient mice. Overall, our observations confirm the complexity of IGF1R in mediating brain signaling responses and suggest that its deficiency negatively impacts brain cells homeostasis and survival by affecting mitochondria and redox homeostasis.

Special Issue “Mitochondria and Brain Disease”

“…The role of mitochondria in ischemic stroke and I/R injury is also discussed by Carinci et al [ 12 ] who comprehensibly review the principal mitochondrial molecular mechanisms that function during the insults and present potential neuroprotective strategies targeting mitochondrial dysfunction and mitochondrial homeostasis. The importance of mitochondria in the cascade of events regulated by the IGF1/IGF1R signalling pathway is also described by Cardoso et al [ 13 ]. In the same line, Lu et al [ 14 ] demonstrate that mitochondrial function is improved in an animal model of epilepsy treated with medicinal plant-derived substances.…”

A novel 28-bp indel inIGF1Rgene associated with growth traits across four Chinese cattle breeds

“…Overexpression of the human IGF1R promotes ligand-dependent neoplastic transformation (Fottner et al ., 2006). The deficiency of IGF1R negatively impacts brain cells homeostasis and survival by affecting mitochondria and redox homeostasis (Cardoso and Moreira, 2021). The above results show that IGF1R gene can affect the occurrence of individual diseases.…”

An Approach to Evaluate the Effective Cytoplasmic Concentration of Bioactive Agents Interacting with a Selected Intracellular Target Protein

“…The supernatants of the cell lysates were applied to denaturing electrophoresis followed by Western blot staining by either anti-Nrf2 (ab31163, Abcam, Cambridge, UK) or anti-Keap1 (ab139729, Abcam) mAb. These antibodies have been successfully used to assess the relative amounts of Nrf2 and Keap1 using Western blot on a number of murine cell types [ 27 , 28 , 29 , 30 , 31 , 32 ]. Sample electrophoresis was performed using standard 10% SDS-PAGE.…”