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Species-specific mitochondria dynamics and metabolism regulate the timing of neuronal development

Ryohei Iwata, Pierre Casimir, Emir Erkol, Leïla Boubakar, Mélanie Planque, Martyna Ditkowska, Katlijn Vints, Suresh Poovathingal, Vaiva Gaspariunaite, Matthew Bird, Nikky Corthout, Pieter Vermeersch, Kristofer Davie, Natalia V. Gounko, Stein Aerts, Bart Ghesquière, Sarah-Maria Fendt, Pierre Vanderhaeghen

Preprint posted on December 27, 2021 https://www.biorxiv.org/content/10.1101/2021.12.27.474246v1

Metabolism regulates developmental timing

Selected by Meng Zhu

Background

 

Background

 

The temporal cost of life events differs significantly between species, resulting in the inter-species variation we see in lifespan. As part of the life cycle, the timing of embryonic development also shows a species-specific pattern. Interestingly, developmental time positively correlates with the species-specific life-span, suggesting fundamental conservation in the mechanisms accounting for species-specific life span. Mammalian species show many similarities in the developmental process and yet divergence in developmental timing. For instance, the gestation time of a mouse embryo is around 1 month, while gestation in humans takes around 10 months.  Two recent studies suggest that in the cases of spinal cord development and somitogenesis, human embryos cost two-fold the time of that of the mouse1,2. The two studies also showed that protein degradation provides a plausible cause for such time divergence.  It has largely been assumed that metabolic differences may play a role in this, but the upstream mechanisms that lead to protein degradation rate change have not yet been explored.

A recent preprint by Diaz-Cuadros et al.20213 (also highlighted by prelight: https://prelights.biologists.com/highlights/metabolic-regulation-of-species-specific-developmental-rates/), supported this idea by showing that overall metabolic rate scales with the developmental time between mouse and human, and that the partial inhibition of  electron transport chain activity –slows down developmental progression.

In this preprint, the authors provide further evidence for the metabolism-developmental timing hypothesis.

 

A recent preprint by Diaz-Caudros et al.20213 (also highlighted by prelight: https://prelights.biologists.com/highlights/metabolic-regulation-of-species-specific-developmental-rates/), supported this idea by showing that overall metabolic rate scales with the developmental time between mouse and human, and that the inhibition of oxidative propargylation – the pathway that produces the ATP most efficiently – inhibits the developmental progression.

 

In this preprint, the authors provide further evidence for the metabolism-developmental timing hypothesis.

 

 

 

Results

 

The authors used cortical neuron development as a model, as the timing of neuron maturation differs significantly between mouse and human (around 2-3 weeks in mouse and >12 months in human).  Previous xenotransplantation experiments showed that the species-specific timing of neuronal maturation is likely caused by cell-intrinsic factor(s). Mitochondrial dynamics have been shown to regulate the neurogenesis process4, but it was unknown whether it regulates the speed of neuronal maturation.

 

The authors first examined mitochondria morphology over the time-course of neuronal maturation in mouse embryos and pluripotent stem cells (PSC) differentiated human neuron progenitors. They found that the progression of mitochondria growth correlated with overall neuronal maturation time. This observation indicates that mitochondria metabolic activity may correspond to developmental timing. To examine this further,  the authors measured oxidative phosphorylation activity, one of the key metabolism processes happening within mitochondria,  by measuring the oxygen consumption rate (OCR). OCR gradually increases as mitochondria grow. More importantly, OCR was > 10 times higher in mouse than in human (Fig). This suggests that the rate of metabolic processes such as oxidative phosphorylation is faster in mouse than in human.

Fig. Oxygen consumption rate is significantly lower in human than in mouse during neuron development.

 

The authors performed glucose-tracer experiments to diagnose which glucose-related metabolic pathways/steps may show differential activities between mouse and human. Firstly, this showed that the level of mitochondrial lactate is significantly higher in human than that of the mouse.   The enrichment of lactate is caused by both the higher secretion rate of lactate and the higher lactate-conversion rate by glucose.  Secondly, the tricarboxylic acid (TCA) cycle rate was lower in human that in the mouse.

 

To test whether the observed differences of metabolic activities may account for species-specific timing for neuronal maturation, the authors inhibited lactate dehydrogenase (LDH), the enzyme that is responsible for pyruvate to lactate conversion. Strikingly, the authors found that the inhibition of LDH increased mitochondria activity and accelerated the maturation process of human neurons by several weeks.

 

Together, these results support that the difference in metabolic activity mediates the species-specific developmental timing.

 

Why did I choose this preprint?

 

This preprint is parallel with another recent preprint (Diaz-Cuadros et al., 2021) and supports the notion in the field that metabolic activity may regulate species-specific developmental timing. However, the two preprints used different systems, and reveal similarities and differences in the upstream metabolic regulation between mouse and human.

Both preprints show that the rate of multiple core metabolic pathways is slower in human than in mouse (TCA cycle, Oxidative phosphorylation). Thus, the slower metabolic rate in human is a general pattern, rather than the selective evolution of specific pathways.

However, different from the case in somitogenesis, where glucose and lactate ratio is similar, a higher lactate content has been found in cortical neuron development. This shows that tissue-specific traits in metabolic composition exist.

 

References

 

 

  1. Matsuda M, Hayashi H, Garcia-Ojalvo J, Yoshioka-Kobayashi K, Kageyama R, Yamanaka Y, Ikeya M, Toguchida J, Alev C, Ebisuya M. Species-specific segmentation clock periods are due to differential biochemical reaction speeds. Science. 2020 Sep 18;369(6510):1450-1455. doi: 10.1126/science.aba7668. PMID: 32943519.

 

  1. Rayon T, Stamataki D, Perez-Carrasco R, Garcia-Perez L, Barrington C, Melchionda M, Exelby K, Lazaro J, Tybulewicz VLJ, Fisher EMC, Briscoe J. Species-specific pace of development is associated with differences in protein stability. Science. 2020 Sep 18;369(6510):eaba7667. doi: 10.1126/science.aba7667. PMID: 32943498; PMCID: PMC7116327.

 

  1. Metabolic regulation of species-specific developmental rates. Margarete Diaz-Cuadros, Teemu P. Miettinen, Dylan Sheedy, Carlos Manlio Díaz García, Svetlana Gapon, Alexis Hubaud, Gary Yellen, Scott R. Manalis, WilliamOldham, Olivier Pourquié bioRxiv 2021.08.27.457974; doi: https://doi.org/10.1101/2021.08.27.457974

 

  1. Iwata R, Casimir P, Vanderhaeghen P. Mitochondrial dynamics in postmitotic cells regulate neurogenesis. Science. 2020 Aug 14;369(6505):858-862. doi: 10.1126/science.aba9760. PMID: 32792401.

 

Posted on: 1st February 2022

doi: https://doi.org/10.1242/prelights.31337

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Author's response

Ryohei Iwata and Pierre Vanderhaeghen shared

  1. What do you think is the physiological, and evolutionary relevance of the higher level of lactate in human developing neurons?

 

In the adult brain, lactate is mostly produced by astrocytes, and transferred to neurons to support neuronal energetic demands and regulate neuronal function (Magistretti and Allaman, 2018). In contrast we find that human developing neurons produce lactate in large quantities, in the absence of astrocytes. This immature state is in many ways reminiscent of the profile of aerobic glycolysis found in embryonic progenitors or cancer cells for instance. This is in line with in vivo functional imaging of the human postnatal brain, which detected high levels of aerobic glycolysis in the developing cortex, in correlation human brain neoteny (Goyal et al., 2014)(Vaishnavi et al., 2010).

We don’t know whether the high levels of lactate production by juvenile human neurons has physiological effects, for instance by contributing to neuronal maturation or plasticity, or if it mostly reflects the immature metabolic state of these neurons.

 

  1. Diaz-Cuadros et al., 2021 also showed that the inhibition of LDH decreased the somitogenesis process. Do you think the inhibition of LDH is a result of accelerated Oxidative phosphorylation,or relates to the concertation of lactate directly?

 

We find that chronic inhibition of LDHA (the LDH isoenzyme that catalyses the conversion of pyruvate into lacate) accelerates the speed of cortical neuron maturation and increased oxidative phosphorylation. LDHA inhibition is known to lead to increased mitochondrial activity through increased Pyruvate availability for mitochondria TCA, which is what we observe in human neurons. Moreover we find that other treatments like PDK inhibition or free fatty acid addition, which increase mitochondria TCA and oxphos, also lead to increased neuronal maturation.

Thus our data suggest that the changes in lactate are less likely to contribute to the effects on neuronal maturation triggered by LDH inhibition. But this would be interesting to explore, especially considering the othert known effects of lactate on adult neuronal function.

 

  1. Is LDH higher expressed in human than in mouse?

 

We don’t know that. LDH is a tetrameric enzyme with isoenzymes composed of different proportions of two common subunits, A and B, LDHA favoring the conversion of pyruvate to lactate, LDHB favoring the conversion of lactate to pyruvate. It will be interesting to compare the levels of LDHA and LDHB during neuronal maturation in various species.

 

  1. Neuronal maturation is much slower in human than in mouse (rather than two-fold in the case of somitogenesis and spinal cord

development). What do you think is the biological significance of this property?

 

The process of cortical pyramidal neuron maturation takes 3–4 weeks in mice, 3–4 months in macaques, while human cortical neurons can mature over a much longer period, up to several years in the prefrontal cortex. This prolonged neuronal maturation in humans is thought to be a major component of human brain neoteny, by which our brain retains juvenile features, such as extended periods of neural plasticity, for much longer periods than other species. Brain neoteny has long been proposed to play a key role in acquiring human-specific cognitive features, for instance by extending critical periods of learning and plasticity. Noteably cortical neurogenesis, ie the process of neuronal generation and specification, is also considerably extended in time in the human embryo (over 4 months instead of six days in the mouse). The heterochrony of human corticogenesis could thus contribute in several ways to human brain expansion, complexification, and functionality. Moreover, changes in the timing and rate of human cortical development, whether consisting of delays or precociousness, may be associated with intellectual deficiency and and autism spectrum disorders.

 

 

  1. Do you think protein degradation rate may account for slower neuronal maturation in human?

 

This is an intriguing question that remains to be addressed. One would first need to determine in different species whether rates of protein turnover correlate with the speed of neuronal development. If so an exciting but challenging experiment would be to test whether increased protein turnover (synthesis and/or degradation) could actually lead to accelerated maturation, as does boosting of mitochondria metabolism.

 

References:

  1. Goyal, M.S., Hawrylycz, M., Miller, J.A., Snyder, A.Z., and Raichle, M.E. (2014). Aerobic glycolysis in the human brain is associated with development and neotenous gene expression. Cell Metab. 19, 49–57.
  2. 2. Magistretti, P.J., and Allaman, I. (2018). Lactate in the brain: From metabolic end-product to signalling molecule. Nat. Rev. Neurosci. 19, 235–249.
  3. 3. Vaishnavi, S.N., Vlassenko, A.G., Rundle, M.M., Snyder, A.Z., Mintun, M.A., and Raichle, M.E. (2010). Regional aerobic glycolysis in the human brain. Proc. Natl. Acad. Sci. U. S. A. 107, 17757–17762.

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