Mitochondrial Dysfunction and Changes in High-Energy Compounds in Different Cellular Models Associated to Hypoxia: Implication to Schizophrenia

Luiz Felipe Souza e Silva,Jéssica Mayumi Camargo Yuzawa,Tatiana Rosado Rosenstock,Mariana Dutra Brito

doi:10.1038/s41598-019-53605-4

Luiz Felipe Souza e Silva, Jéssica Mayumi Camargo Yuzawa + Show 2 more

Open Access

https://doi.org/10.1038/s41598-019-53605-4

Copy DOI

Abstract

Schizophrenia (SZ) is a multifactorial mental disorder, which has been associated with a number of environmental factors, such as hypoxia. Considering that numerous neural mechanisms depends on energetic supply (ATP synthesis), the maintenance of mitochondrial metabolism is essential to keep cellular balance and survival. Therefore, in the present work, we evaluated functional parameters related to mitochondrial function, namely calcium levels, mitochondrial membrane potential, redox homeostasis, high-energy compounds levels and oxygen consumption, in astrocytes from control (Wistar) and Spontaneously Hypertensive Rats (SHR) animals exposed both to chemical and gaseous hypoxia. We show that astrocytes after hypoxia presented depolarized mitochondria, disturbances in Ca2+ handling, destabilization in redox system and alterations in ATP, ADP, Pyruvate and Lactate levels, in addition to modification in NAD+/NADH ratio, and Nfe2l2 and Nrf1 expression. Interestingly, intrauterine hypoxia also induced augmentation in mitochondrial biogenesis and content. Altogether, our data suggest that hypoxia can induce mitochondrial deregulation and a decrease in energy metabolism in the most prevalent cell type in the brain, astrocytes. Since SHR are also considered an animal model of SZ, our results can likewise be related to their phenotypic alterations and, therefore, our work also allow an increase in the knowledge of this burdensome disorder.

Highlights

Schizophrenia (SZ) is a multifactorial mental disorder, which has been associated with a number of environmental factors, such as hypoxia
In the present work, we evaluated in astrocytes from Spontaneously Hypertensive Rats (SHR animals) and astrocytes exposed to chemical and gaseous hypoxia functional parameters related to mitochondrial function, namely calcium handling, mitochondrial membrane potential, redox homeostasis, oxygen consumption and ATP, ADP, Pyruvate, Lactate and NAD+/ NADH levels, in addition to gene expression and protein levels related to mitochondrial metabolism
Since we demonstrated that astrocytes submitted to hypoxia present changes in calcium handling, mitochondria membrane potential and redox homeostasis, in addition to oxygen consumption (See Supplementary Fig. 2SS) and lipid peroxidation (See Supplementary Fig. 1SS), we investigated whether the increase in mitochondrial biogenesis and content could represent a compensation to keep cellular energy metabolism

Summary

Introduction

Schizophrenia (SZ) is a multifactorial mental disorder, which has been associated with a number of environmental factors, such as hypoxia. A study designed by Mayoral and collaborators using rodents showed that exposure to chronic hypoxia may lead to loss of tissue volume, decreased myelination and increased ventricles[10] Many of these abnormalities are observed schizophrenic patients brains[11,12,13]. In the present work, we evaluated in astrocytes from Spontaneously Hypertensive Rats (SHR animals) (model of intrauterine hypoxia) and astrocytes exposed to chemical and gaseous hypoxia functional parameters related to mitochondrial function, namely calcium handling, mitochondrial membrane potential, redox homeostasis, oxygen consumption and ATP, ADP, Pyruvate, Lactate and NAD+/ NADH levels, in addition to gene expression and protein levels related to mitochondrial metabolism. Intrauterine and chemical hypoxia induce changes in ATP, ADP, Pyruvate and Lactate levels and NAD+/NADH ratio, despite an intensification of mitochondrial biogenesis and mitochondrial content

Methods

Results

Conclusion