H2O2 Signalling Pathway: A Possible Bridge between Insulin Receptor and Mitochondria

Abstract

This review is focused on the mechanistic aspects of the insulin-induced H2O2 signalling pathway in neurons and the molecules affecting it, which act as risk factors for developing central insulin resistance. Insulin-induced H2O2 promotes insulin receptor activation and the mitochondria act as the insulin-sensitive H2O2 source, providing a direct molecular link between mitochondrial dysfunction and irregular insulin receptor activation. In this view, the accumulation of dysfunctional mitochondria during chronological ageing and Alzheimer’s disease (AD) is a risk factor that may contribute to the development of dysfunctional cerebral insulin receptor signalling and insulin resistance. Due to the high significance of insulin-induced H2O2 for insulin receptor activation, oxidative stress-induced upregulation of antioxidant enzymes, e.g., in AD brains, may represent another risk factor contributing to the development of insulin resistance. As insulin-induced H2O2 signalling requires fully functional mitochondria, pharmacological strategies based on activating mitochondria biogenesis in the brain are central to the treatment of diseases associated with dysfunctional insulin receptor signalling in this organ.

Effects of thiol antioxidant β-mercaptoethanol on diet-induced obese mice

“…Both findings are in complete agreement with the literature that adequate level of pro-oxidants (e.g. peroxides) is essential for proper insulin signaling transduction 10–17 . The reduction of insulin sensitivity could be related to the over-efficient ROS scavenging by the thiol antioxidants, as evidenced by our in vitro data that BME could directly reduce insulin-stimulated Akt phosphorylation in cultured liver cells.…”

“…Diverse pharmacologic and genetic approaches to decrease ROS have been shown to reduce obesity and improve insulin reactivity 4–6 , although studies on the effect of dietary antioxidants remain inconclusive 7–9 . Among the vast literature about the therapeutic effect of antioxidant supplements on obesity, few have addressed the fact that hydrogen peroxide (H 2 O 2 ), a mild ROS by itself but a precursor for several strongly damaging radicals, is also an important physiological messenger for insulin signaling 10–13 . As a matter of fact, H 2 O 2 is essential for insulin-mediated metabolic effects in adipocytes, including stimulation of glucose transport and lipid synthesis, as well as suppression of lipolysis 14–16 .…”

Mitochondrial aquaporin-8 is involved in SREBP-controlled hepatocyte cholesterol biosynthesis

“…Los SREBP-1a y SREBP-2 no son solo modulados por los niveles intracelulares de colesterol, sino que también pueden ser activados por fosforilación dependiente de las MAPK pertenecientes a la subfamilia ERK (Kotzka y col., 2000). La acción colesterogénica de la hormona insulina en células hepáticas puede ser en parte explicado por este mecanismo vía activación de las ERK/MAPK (Pomytkin, 2012…”

Advances around technologies investigating mitochondrial function and insights gained by their applications

“…Amplex red was used by Pomytkin to show insulin‐treated neuronal cell release H 2 O 2 from the mitochondrion. The response was surprisingly rapid, and occurred immediately after insulin treatment, suggesting it is not mediated through activation of nuclear genes (Figure ).…”

“…(a) Very rapid rise in H 2 O 2 signal from the mitochondrion after insulin treatment, measured by applying Amplex Red in cultured cerebellar granule neurons. (b) Control of insulin receptor phosphorylation by H 2 O 2 (from Pomytkin with permission). MITO , mitochondrion; P, phosphate.…”