Paradoxical neuronal hyperexcitability in a mouse model of mitochondrial pyruvate import deficiency

Abstract

Neuronal excitation imposes a high demand of ATP in neurons. Most of the ATP derives primarily from pyruvate-mediated oxidative phosphorylation, a process that relies on import of pyruvate into mitochondria occuring exclusively via the mitochondrial pyruvate carrier (MPC). To investigate whether deficient oxidative phosphorylation impacts neuron excitability, we generated a mouse strain carrying a conditional deletion of MPC1, an essential subunit of the MPC, specifically in adult glutamatergic neurons. We found that, despite decreased levels of oxidative phosphorylation and decreased mitochondrial membrane potential in these excitatory neurons, mice were normal at rest. Surprisingly, in response to mild inhibition of GABA mediated synaptic activity, they rapidly developed severe seizures and died, whereas under similar conditions the behavior of control mice remained unchanged. We report that neurons with a deficient MPC were intrinsically hyperexcitable as a consequence of impaired calcium homeostasis, which reduced M-type potassium channel activity. Provision of ketone bodies restored energy status, calcium homeostasis and M-channel activity and attenuated seizures in animals fed a ketogenic diet. Our results provide an explanation for the seizures that frequently accompany a large number of neuropathologies, including cerebral ischemia and diverse mitochondriopathies, in which neurons experience an energy deficit.

CKII Control of Axonal Plasticity Is Mediated by Mitochondrial Ca2+ via Mitochondrial NCLX

“…Importantly, ROS has been shown to increase the non-inactivating Na + current (INaP) and decrease the voltage-gated K + channel functions, notably the transient A-type and the delayed rectifying K + current, which can significantly contribute to network hyperexcitability [ 52 , 57 , 58 , 59 ]. Along the same line of enquiry, a recent study showed that deficient oxidative phosphorylation in a mouse strain carrying a conditional deletion of MPC1, an essential subunit of the mitochondrial pyruvate carrier, developed seizures in response to mild inhibition of GABA-mediated synaptic activity [ 60 ]. Neurons from these deficient MPC1 mice were intrinsically hyperexcitable as a consequence of impaired calcium homeostasis, which reduced the M-type potassium channel activity [ 60 ].…”

“…Along the same line of enquiry, a recent study showed that deficient oxidative phosphorylation in a mouse strain carrying a conditional deletion of MPC1, an essential subunit of the mitochondrial pyruvate carrier, developed seizures in response to mild inhibition of GABA-mediated synaptic activity [ 60 ]. Neurons from these deficient MPC1 mice were intrinsically hyperexcitable as a consequence of impaired calcium homeostasis, which reduced the M-type potassium channel activity [ 60 ]. Thus, it is possible that the intrinsic hyperexcitability found in hippocampal neurons derived from NCLX-KO mice could arise from reduced activity of voltage-gated K + currents.…”

Neuroglobin deficiency increases seizure susceptibility but does not affect basal behavior in mice

“…Reducing energy capacity in glutamatergic neurones by conditional KO of the mitochondrial pyruvate carrier 1 (Mpc1) in glutamatergic but not GABAergic neurones can lead to increased seizures after GABA receptor antagonism by pentylenetetrazol or by KA-induced glutamatergic stimulation (De La Rossa et al, 2022). Also reducing metabolism in glutamate and GABA neurones by using brain-specific pyruvate dehydrogenase E1 subunit alpha 1 (Pdha1) KO mice can lead to increased susceptibility to seizures due to dysfunctional excitability in glutamatergic neurones (Jakkamsetti et al, 2019).…”

Mitochondrial Ca2+ Signaling and Bioenergetics in Alzheimer’s Disease

“…However, a blunted mitochondrial Ca 2+ signal can also be detrimental for both the consequent decreased ATP production and the altered cytosolic Ca 2+ buffering ( Figure 1 B and Figure 2 ). For example, it has been recently shown that in neurons downregulated for either MCU or mitochondrial pyruvate carriers 1 (MPC1), as a consequence of blunted mitochondrial Ca 2+ uptake, the cytosolic Ca 2+ level was significantly higher compared to the control, contributing to neuronal hyperexcitability [ 66 , 138 ].…”

“…Finally, diet and exercise can enhance/modulate mitochondrial function. As an example, ketogenic diets have been reported to rescue neuronal Ca 2+ handling dysfunction, by overcoming the mitochondria hypometabolism caused by impaired pyruvate import [ 138 ].…”