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

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.

Neuron-specific protein network mapping of autism risk genes identifies shared biological mechanisms and disease relevant pathologies

“…We found that Taok2 KO mouse neurons had altered mitochondrial morphology with a reduction in category 1 and 3 mitochondria, which show more typical mitochondria morphology, and an increase in category 2 mitochondria at their synapses (Fig. 3h, i) 63 . Category 2 mitochondria have enlarged non-contiguous mitochondrial cristae 63 , which can cause reduced oxidative phosphorylation and prevent proper translation and insertion of inner membrane proteins 64, 65 .…”

“…We examined the morphology of mitochondria in vivo from electron microscopy (EM) images from WT and Taok2 KO mouse brains (Richter et al, 2019). Taok2 KO mouse neurons had altered mitochondrial morphology with a reduction in category 1 and 3 mitochondria (typical morphology), and an increase in category 2 mitochondria at synapses (Figure 3H and 3I) (Da Costa et al, 2018). Category 2 mitochondria indicate enlarged non-contiguous mitochondrial cristae, which can reduce oxidative phosphorylation and cause aberrant mitochondrial protein translation (John et al, 2005; Schmidt et al, 2010).…”

“…3h, i) 63 . Category 2 mitochondria have enlarged non-contiguous mitochondrial cristae 63 , which can cause reduced oxidative phosphorylation and prevent proper translation and insertion of inner membrane proteins 64, 65 . We extended our mouse studies to examine whether TAOK2 regulates mitochondrial/metabolic processes in human induced pluripotent stem cell (iPSC)-derived NGN2-neurons.…”

Human Induced Pluripotent Stem Cell-Derived TDP-43 Mutant Neurons Exhibit Consistent Functional Phenotypes Across Multiple Gene Edited Lines Despite Transcriptomic and Splicing Discrepancies

“…Similarly, measurement of mitochondrial size and circularity from TEM images was carried out in ImageJ. Assessment of gross mitochondrial structure was performed manually as previously described ( Costa et al, 2018 ). Briefly, 30 micrographs were randomly taken for each cell type, and at least 100 mitochondria were counted and labeled either “normal” or “altered.” Normal mitochondria were defined as exhibiting organized and parallel cristae that ran perpendicular to each mitochondrion’s primary axis.…”

Glycolysis mediates neuron specific histone acetylation in valproic acid-induced human excitatory neuron differentiation

“…Interestingly, our data showed a rapid impairment of mitochondrial function and elevation of glycolysis in human NPCs following VPA treatment. One study has reported ultrastructural disorganization of mitochondria in human NPCs following VPA treatment ( Costa et al, 2018 ). Our data not only confirmed the morphological change of mitochondria, but also demonstrated an impairment of respiratory complex activity and increase of glycolysis in human NPCs by VPA.…”