Metabolic commitment to human motor neurons is characterized by mitochondrial depletion and pyruvate rewiring

Abstract

Mitochondrial remodelling is a key feature of neurogenesis in cortical and hippocampal neuronal lineages, yet the temporal control of organellar homeostasis in developing human motor neurons remains poorly understood. Here, we generated a high-resolution temporal resource integrating proteomics, metabolomics, and mitochondrial characterization across human iPSC-to-motor neuron differentiation. This analysis revealed prolonged mitochondrial depletion during early neurogenesis, characterized by reduced mitochondrial content, mitochondrial fragmentation, and lysosome-dependent turnover. This state persisted throughout the neural progenitor stage and was followed by recovery of mitochondrial content during neuronal maturation. During this transition, pyruvate utilization shifted from pyruvate carboxylation towards pyruvate dehydrogenase-dependent oxidation. Pharmacological manipulation of pyruvate partitioning demonstrated that this metabolic switch is required for human neuronal differentiation. Our findings establish a temporal framework for the metabolic control of human motor neuron differentiation and reveal a progenitor-specific state linking mitochondrial depletion to pyruvate metabolism.

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BibTeX

@misc{torregrosamunumer2026metabolic,
  title = {{Metabolic commitment to human motor neurons is characterized by mitochondrial depletion and pyruvate rewiring}},
  author = {R. Torregrosa-Munumer and J. Turkia and D. Spirin and J. Kvist and J. Saarimaki-Vire and S. Povea-Cabello and R. Ermis and J. Pennonen and E. Kuuluvainen and T. Otonkoski and V. Hietakangas and T. G. McWilliams and E. Fernandez-Vizarra and P. Katajisto and H. Tyynismaa},
  howpublished = {bioRxiv},
  year = {2026},
  month = oct,
  doi = {10.64898/2026.10.05.756667},
  url = {https://www.biorxiv.org/content/10.64898/2026.10.05.756667v1},
  note = {CC BY},
}

RIS

TY  - UNPB
TI  - Metabolic commitment to human motor neurons is characterized by mitochondrial depletion and pyruvate rewiring
AU  - R. Torregrosa-Munumer
AU  - J. Turkia
AU  - D. Spirin
AU  - J. Kvist
AU  - J. Saarimaki-Vire
AU  - S. Povea-Cabello
AU  - R. Ermis
AU  - J. Pennonen
AU  - E. Kuuluvainen
AU  - T. Otonkoski
AU  - V. Hietakangas
AU  - T. G. McWilliams
AU  - E. Fernandez-Vizarra
AU  - P. Katajisto
AU  - H. Tyynismaa
PY  - 2026
DA  - 2026/10/05
PB  - bioRxiv
DO  - 10.64898/2026.10.05.756667
UR  - https://www.biorxiv.org/content/10.64898/2026.10.05.756667v1
AB  - Mitochondrial remodelling is a key feature of neurogenesis in cortical and hippocampal neuronal lineages, yet the temporal control of organellar homeostasis in developing human motor neurons remains poorly understood. Here, we generated a high-resolution temporal resource integrating proteomics, metabolomics, and mitochondrial characterization across human iPSC-to-motor neuron differentiation. This analysis revealed prolonged mitochondrial depletion during early neurogenesis, characterized by reduced mitochondrial content, mitochondrial fragmentation, and lysosome-dependent turnover. This state persisted throughout the neural progenitor stage and was followed by recovery of mitochondrial content during neuronal maturation. During this transition, pyruvate utilization shifted from pyruvate carboxylation towards pyruvate dehydrogenase-dependent oxidation. Pharmacological manipulation of pyruvate partitioning demonstrated that this metabolic switch is required for human neuronal differentiation. Our findings establish a temporal framework for the metabolic control of human motor neuron differentiation and reveal a progenitor-specific state linking mitochondrial depletion to pyruvate metabolism.
ER  -

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