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

Rossa, Andres De la; Laporte, Marine H.; Astori, Simone; Marissal, Thomas; Montessuit, Sylvie; Sheshadri, Preethi; Ramos-Fernández, Eva; Méndez, Pablo; Khani, Abbas; Quairiaux, Charles; Taylor, Eric B.; Rutter, Jared; Nunes, José Manuel; Carleton, Alan; Duchen, Michael R.; Sandi, Carmen; Martinou, Jean‐Claude

doi:10.1101/2020.12.22.423903

Cited by 4 publications

(5 citation statements)

References 59 publications

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“…These results suggest that newborn neurons might have a higher metabolic flexibility than previously thought if their preferential metabolic pathway is blocked. In line with this, it has been shown that several types of mature neurons are indeed able to sustain their functions by shifting their metabolism to other substrates, which can fuel OXPHOS when MPC is inhibited (59,64,65). We show that MPC1 cKO NSPCs are able to generate mature neurons in vitro and in vivo.…”

Section: Discussionsupporting

confidence: 80%

Mitochondrial pyruvate metabolism regulates the activation of quiescent adult neural stem cells

et al. 2023

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Cellular metabolism is important for adult neural stem/progenitor cell (NSPC) behavior. However, its role in the transition from quiescence to proliferation is not fully understood. We here show that the mitochondrial pyruvate carrier (MPC) plays a crucial and unexpected part in this process. MPC transports pyruvate into mitochondria, linking cytosolic glycolysis to mitochondrial tricarboxylic acid cycle and oxidative phosphorylation. Despite its metabolic key function, the role of MPC in NSPCs has not been addressed. We show that quiescent NSPCs have an active mitochondrial metabolism and express high levels of MPC. Pharmacological MPC inhibition increases aspartate and triggers NSPC activation. Furthermore, genetic Mpc1 ablation in vitro and in vivo also activates NSPCs, which differentiate into mature neurons, leading to overall increased hippocampal neurogenesis in adult and aged mice. These findings highlight the importance of metabolism for NSPC regulation and identify an important pathway through which mitochondrial pyruvate import controls NSPC quiescence and activation.

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Section: Discussionsupporting

confidence: 80%

Mitochondrial pyruvate metabolism regulates the activation of quiescent adult neural stem cells

et al. 2023

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“…These results suggest that newborn neurons might have a higher metabolic flexibility than previously thought if their preferential metabolic pathway is blocked. In line with this, it has been shown that several types of mature neurons are indeed able to sustain their functions by shifting their metabolism to other substrates, which can fuel OXPHOS when MPC is inhibited (DeLaRossa et al, 2022;Divakaruni et al, 2017;Ghosh et al, 2016). Indeed, we show that MPC1 ckO NSPCs are able to generate mature neurons in vitro and in vivo.…”

Section: Discussionsupporting

confidence: 86%

Mitochondrial pyruvate metabolism regulates the activation of quiescent adult neural stem cells

Petrelli

Scandella

Montessuit

et al. 2022

Preprint

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Cellular metabolism is important for adult neural stem/progenitor cell (NSPC) behavior. However, its role in the transition from quiescence to proliferation is not fully understood. We here show that the mitochondrial pyruvate carrier (MPC) plays a crucial and unexpected part in this process. MPC transports pyruvate into mitochondria, linking cytosolic glycolysis to mitochondrial tricarboxylic acid cycle (TCA) and oxidative phosphorylation (OXPHOS). Despite its metabolic key function, the role of MPC in NSPCs has not been addressed. We show that quiescent NSPCs have an active mitochondrial metabolism and express high levels of MPC. Pharmacological MPC inhibition increases aspartate and triggers NSPC activation. Furthermore, genetic MPC-ablation in vivo also activates NSPCs, which differentiate into mature neurons, leading to overall increased hippocampal neurogenesis in adult and aged mice. These findings highlight the importance of metabolism for NSPC regulation and identify a novel pathway through which mitochondrial pyruvate import controls NSPC quiescence and activation.

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“…This is in line with seizure development being a consequence of dysregulations generated either by reducing inhibitory (γ‐aminobutyric‐acid; GABAergic) or increasing excitatory (glutamatergic) signaling (Paz & Huguenard, 2015). 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).…”

Section: Discussionmentioning

confidence: 99%

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

Gøtzsche

Hundahl

Hay‐Schmidt

2022

J of Neuroscience Research

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Neuroglobin (Ngb) is found in the neurones of several different brain areas and is known to bind oxygen and other gaseous molecules and reactive oxygen species (ROS) in vitro, but it does not seem to act as a respiratory molecule for neurones.Using male and female Ngb-knockout (KO) mice, we addressed the role of Ngb in neuronal brain activity using behavioral tests but found no differences in general behaviors, memory processes, and anxiety−/depression-like behaviors. Oxidative stress and ROS play key roles in epileptogenesis, and oxidative injury produced by an excessive production of free radicals is involved in the initiation and progression of epilepsy. The ROS binding properties led us to hypothesize that lack of Ngb could affect central coping with excitatory stimuli. We consequently explored whether exposure to the excitatory molecule kainate (KA) would increase severity of seizures in mice lacking Ngb. We found that the duration and severity of seizures were increased, while the latency time to develop seizures was shortened in Ngb-KO compared to wildtype adult female mice. Consistently, c-fos expression after KA was significantly increased in Ngb-KO mice in the amygdala and piriform cortex, regions rich in Ngb and known to be centrally involved in seizure generation. Moreover, the measured c-fos expression levels were correlated with seizure susceptibility. With these new findings combined with previous studies we propose that Ngb could constitute an intrinsic defense mechanism against neuronal hyperexcitability and oxidative stress by buffering of ROS in amygdala and other Ngb-containing brain regions.

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

Cited by 4 publications

References 59 publications

Mitochondrial pyruvate metabolism regulates the activation of quiescent adult neural stem cells

Mitochondrial pyruvate metabolism regulates the activation of quiescent adult neural stem cells

Mitochondrial pyruvate metabolism regulates the activation of quiescent adult neural stem cells

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

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