Deformation of Mitochondrial Cristae in Human Neural Progenitor Cells Exposed to Valproic Acid.

Rodrigo M Da Costa,Stevens K Rehen,Karina Karmirian

doi:10.1590/0001-3765201820170762

Abstract

Neural development represents a dynamic process where mitochondrial integrity is decisive for neuronal activity. Structural changes in these organelles may be related to neurological disorders. Valproic acid (VPA) is an anticonvulsive drug commonly used for epilepsy treatment and its use is associated to increased risk of neuropsychiatric disorders. Recently we showed changes in shape and membrane potential in mitochondria from human neural progenitor cells (NPCs) exposed to VPA (da Costa et al. 2015). Here, we applied transmission electron microscopy and electron tomography to evaluate mitochondrial damage caused by VPA in NPCs. Results showed mitochondrial cristae disorganization in a dose dependent manner. Disturbance in mitochondrial ultrastructure may influence metabolism, leading to synaptic plasticity and neurogenesis impairment. These data contribute to understanding VPA exposure potential effects on brain development.

Highlights

Mitochondria are organelles that contribute significantly to proper development of central nervous system
Our results revealed that naive neural progenitor cells (NPCs) presented highly organized mitochondrial cristae with regular thickness and electron density (Figure 1a)
Mitochondria presented obvious structural deformations in the presence of Valproic acid (VPA) compared to control; it is possible to find either normal or altered mitochondria in all four conditions addressed in this work

Summary

Introduction

Mitochondria are organelles that contribute significantly to proper development of central nervous system. Neuronal differentiation and health depend on the functional integrity of mitochondria due to high level of cellular energy required (Levytskyy et al 2016, Li et al 2004, Robicsek et al 2013). Mitochondrial dysfunction, on the other hand, affects neuronal metabolism as well as axonal transport, neurotransmitter release and synaptic plasticity (Jurata et al 2006, Park et al 2010, Rossignol and Frye 2012). Mitochondrial dysfunction is commonly associated to neuropsychiatric disorders due to defects in neurotransmitter release and cell redox signaling (Arun et al 2016, Tait and Green 2012). Ultrastructural analysis of rats’ hippocampus in pentylenetetrazol (PTZ)-induced status epilepticus showed alterations in mitochondrial morphology, suggesting a dysfunction related to epileptic pathophysiology (Zhvania et al 2015).

Methods

Results

Conclusion