Pas Kinase Deficiency Triggers Antioxidant Mechanisms in the Liver

P Dongil,E Alvarez,A Pérez-García,C Sanz,E Blazquez,C Herrero-De-Dios,V Hurtado-Carneiro

doi:10.1038/s41598-018-32192-w

Abstract

Metabolic dysfunction in the liver is the cause of numerous pathologies, which are associated with an altered redox state. PASK (PAS Domain Kinase) is a nutrient and bioenergetic sensor. We contend that PASK could act as an oxidative stress sensor in liver and/or control the metabolic balance, playing a role in the mitochondrial homeostasis. Using PASK-deficient mice, we observed that PASK deficiency promotes antioxidant response mechanisms: a lower production of ROS/RNS under non-fasting conditions, overexpression of genes coding to ROS-detoxifying enzymes and mitochondrial fusion proteins (MnSod Gpx, Mfn1 and Opa1), coactivator Ppargc1a, transcription factors (Pparg and FoxO3a) and deacetylase Sirt1. Also, under fasting conditions, PASK deficiency induced the overexpression of Ppargc1a, Ppara, Pparg, FoxO3a and Nrf2 leading to the overexpression of genes coding to antioxidant enzymes such as MnSOD, Cu/ZnSOD, GPx, HO1 and GCLm. Additionally, inducing PINK1 involved in cell survival and mitophagy. These changes kept ROS steady levels and improved the regenerative state. We suggest a new role for PASK as a controller of oxidative stress and mitochondrial dynamics in the liver. In fact, antioxidant response is PASK dependent. PASK-targeting could therefore be a good way of reducing the oxidative stress in order to prevent or treat liver diseases.

Highlights

Food intake initiates mitochondrial oxidative phosphorylation for producing ATP and supporting normal cellular function and metabolic homeostasis, mitochondrial electron transport is the major intracellular source of reactive oxygen species (ROS) or “free radicals”[1,2]
Per-Arnt-Sim Kinase (PASK) deficiency, under basal conditions, increased the expression of coactivator Ppargc1a, transcription factors such as Pparg and FoxO3a, and activators such as deacetylase Sirt[1], all of which are involved in the regulation of oxidative metabolism and mitochondrial biogenesis
PGC1a and SIRT1 protein levels were not modified, SIRT1 location was mainly nuclear. The stimulation of this pathway was observed at the level of the overexpression of the ROS-detoxifying enzymes Manganese superoxide dismutase (MnSOD) and Glutathione Peroxidase (GPx) and confirmed by a lower production of ROS

Summary

Introduction

Food intake initiates mitochondrial oxidative phosphorylation for producing ATP (adenosine triphosphate) and supporting normal cellular function and metabolic homeostasis, mitochondrial electron transport is the major intracellular source of ROS or “free radicals”[1,2]. An exacerbated ROS production and/or an altered antioxidant mechanism could trigger oxidative stress, being harmful and highly toxic to the cell[4,6]. Mitochondria are sources of reactive oxygen species (ROS) and display a continuous processes of fusion and fission resulting in a mitochondrial dynamic that maintain their homeostasis in order to repair different damage[7,8,9]. The liver has metabolic machinery for meeting energy demands during normal physiology, such as glycolysis and mitochondrial oxidative phosphorylation. This condition makes it more susceptible to oxidative stress www.nature.com/scientificreports/. A common characteristic of many chronic liver diseases is nearly always an increase in oxidative stress, regardless of the cause of the disorder[12]

Methods

Results

Discussion

Conclusion