UL12.5 mice brain and UL12.5 neurons were differentiated from 90D iPSCs rna-seq

Mitochondrial DNA (mtDNA) mutations and/or depletion are implicated in
epilepsy and many neurodegenerative diseases. However, systematic
investigation into how mtDNA alterations relate to epilepsy and
neural degeneration is needed. Here, we established a mouse model in which
mtDNA depletion is induced by the Herpes Simplex Virus Type 1 (HSV-1)
protein UL12.5 in the brain led to an epileptic phenotype
characterized by abnormal electroencephalography (EEG) patterns
and increased neural excitability in hippocampus. We
also found that UL12.5 mediated mtDNA depletion in neurons
in vitro (rho-) causes epilepsy–like abnormal EEG.
Caloric restriction (CR) or glucose restriction (GR) is a
strategy proven to reduce epileptic activity, however GR
mimetic 2-deoxy-D-glucose (2-DG),
induced degeneration in mtDNA depleted neurons.
Mechanistically, mtDNA depletion increased
mitochondria-endoplasmic reticulum (ER) contacts,
facilitating GR-induced mitochondrial calcium overload.
Rho- neurons did not show changes in mitochondrial motility or
membrane potential. Our study revealed an unexpected axis of mtDNA
depletion, ER-mitochondrial contacts, and calcium overload in the rho-
neuron model. Fasting-induced GR causes early motor dysfunction,
accelerates epilepsy progression, and worsens neurodegeneration in UL12.5
mice. Importantly, the IP3R inhibitor 2-APB blocks the neurodegeneration
induced by fasting. This is the first description of animal and neuronal
models of mitochondrial epilepsy. Our findings with these models
suggest that GR may not be a viable clinical intervention in
patients with mtDNA depletion.