The Redox Communication Network as a Regulator of Metabolism

Abstract

Key tissues are dysfunctional in obesity, diabetes, cardiovascular disease, fatty liver and other metabolic diseases. Focus has centered on individual organs as though each was isolated. Attention has been paid to insulin resistance as the key relevant pathosis, particularly insulin receptor signaling. However, many tissues play important roles in synergistically regulating metabolic homeostasis and should be considered part of a network. Our approach identifies redox as an acute regulator of the greater metabolic network. Redox reactions involve the transfer of electrons between two molecules and in this work refer to commonly shared molecules, reflective of energy state, that can readily lose electrons to increase or gain electrons to decrease the oxidation state of molecules including NAD(P), NAD(P)H, and thiols. Metabolism alters such redox molecules to impact metabolic function in many tissues, thus, responding to anabolic and catabolic stimuli appropriately and synergistically. It is also important to consider environmental factors that have arisen or increased in recent decades as putative modifiers of redox and reactive oxygen species (ROS) and thus metabolic state. ROS are highly reactive, controlled by the thiol redox state and influence the function of thousands of proteins. Lactate (L) and pyruvate (P) in cells are present in a ratio of about 10 reflective of the cytosolic NADH to NAD ratio. Equilibrium is maintained in cells because lactate dehydrogenase is highly expressed and near equilibrium. The major source of circulating lactate and pyruvate is muscle, although other tissues also contribute. Acetoacetate (A) is produced primarily by liver mitochondria where β-hydroxybutyrate dehydrogenase is highly expressed, and maintains a ratio of β-hydroxybutyrate (β) to A of about 2, reflective of the mitochondrial NADH to NAD ratio. All four metabolites as well as the thiols, cysteine and glutathione, are transported into and out of cells, due to high expression of relevant transporters. Our model supports regulation of all collaborating metabolic organs through changes in circulating redox metabolites, regardless of whether change was initiated exogenously or by a single organ. Validation of these predictions suggests novel ways to understand function by monitoring and impacting redox state.

Assessing Different Temporal Scales of Calcium Dynamics in Networks of Beta Cell Populations

“…The recently emerging fields of network physiology and network medicine show great potential to address such issues and to provide new insights into how global behavior at the organism level can arise out of micro-mechanisms on the cellular and tissue level ( Bashan et al, 2012 ; Ivanov et al, 2016 ). Metabolic systems make excellent candidates for being studied by these novel interdisciplinary approaches ( Zavala et al, 2019 ; Corkey and Deeney, 2020 ; Martinez et al, 2020 ). Understanding how the multimodal activity of beta cells acts in synchrony and integrates to the organ level, how heterologous interactions with other islet cells affect the pancreatic output, how the complementary action of other hormones contributes to the dynamic crosstalk between metabolic organs, and how all these pathways are impaired in diabetes, are some of the main questions in islet and in specific metabolic diseases research ( Rorsman and Ashcroft, 2018 ; Rutter et al, 2020 ).…”

Redox Homeostasis in Poultry: Regulatory Roles of NF-κB

“…Redox biology is a very quickly developing area of modern biological sciences, and roles of redox homeostasis in health and disease have recently received tremendous attention [ 1 , 2 , 3 , 4 , 5 , 6 ]. There are a range of redox pairs in cells/tissues responsible for redox homeostasis maintenance/regulation.…”

“…Indeed, oxidation of SH groups in Cys of Keap1 or phosphorylation of IκB are important triggers for nuclear translocation and activation of Nrf2 and NF-κB—important players in the redox homeostasis regulation [ 6 ]. In particular, a recent model suggests regulation of all collaborating metabolic organs in the body through changes in circulating redox metabolites [ 5 ].…”

Redox Homeostasis in Pancreatic β-Cells: From Development to Failure

“…Metabolism of β-cells adjusts to higher supply and fuel availability, increasing operating flux capacity and changing characterization of mitochondrial function and overall metabolism. Redox systems then adapt and respond to these changes by altered intracellular redox communication among pyridine nucleotides, ROS and thiols [ 143 ]. Rapid/chronic responses to nutrient intake can be observed further through the blood redox metabolome, thus exceeding intracellular compartments [ 143 ].…”