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

Abstract

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.

Microglial control of neuronal development via somatic purinergic junctions

“…The important role of neuronal mitochondria in developmental and adult neurogenesis has become evident over the last years (Arra ´zola et al, 2019;Khacho and Slack, 2018;Rangaraju et al, 2019). Mitochondrial metabolism fundamentally regulates developmental and adult neurogenesis and differentiation (Beckervordersandforth, 2017;Lorenz and Prigione, 2017;Petrelli et al, 2022), and mitochondrial structural dynamics of postmitotic neurons have been shown to drive developmental neurogenesis (Iwata et al, 2020), being instrumental for cell fate decisions at the same time (Bhola and Letai, 2016). Mitochondria are also critical for injury-related responses in the developing brain (Hagberg et al, 2014) through induction of programmed cell death (Yamaguchi and Miura, 2015) or morphogenesis of neurons (Kimura and Murakami, 2014).…”

Waking up neural stem cells through inhibition of mitochondrial pyruvate import

“…However, innate NSPC pools are preserved in specific brain regions throughout an individual's lifetime. Petrelli et al [1] . recently reported that inhibiting mitochondrial pyruvate import stimulated NSPCs to transition from a quiescent state to an active state, thereby promoting neurogenesis in both young and middle‐aged mice.…”

Mitochondrial respiration and dynamics of in vivo neural stem cells

“…However, these transcriptional changes do not necessarily translate into proteomic differences ( Wani et al, 2022 ), and more-detailed analyses of metabolic requirements during specific NSC transitions have revealed a more complex picture. For example, deletion of the mitochondrial pyruvate carrier (MPC1), which is involved in the import of the end-product of glycolysis, pyruvate, into the mitochondria promotes both NSC activation from quiescence and differentiation into postmitotic neurons, but does not affect proliferation of activated NSCs itself ( Petrelli et al, 2022 preprint). In contrast, long-term depletion of the mitochondrial transcription factor A (TFAM) mostly affects the self-renewal and survival of intermediate progenitor cells, a highly proliferative transient NSC stage shortly after reactivation ( Beckervordersandforth et al, 2017 ).…”

“…In contrast, decreased proliferation of hippocampal NSCs has also been observed upon aberrant mitochondrial fragmentation due to mutation of Mfn1 and Mfn2 ( Khacho et al, 2016 ), suggesting roles of these different GTPases beyond mitochondrial fission and/or fusion, or an as yet incomplete understanding of the complex transitions these adult NSCs undergo. It is still unclear, for example, whether the mitochondria of in vivo quiescent NSCs are fragmented and immature, as observed in vitro ( Cai et al, 2021 ; Petrelli et al, 2022 preprint), or whether they have a fused or clustered morphology akin to Drosophila ( Fig. 3 C,E) ( Endow et al, 2019 ).…”