Pennonen, J. | Search bioRxiv

bioRxiv2026

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

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.

cell biology↗

bioRxiv2019

CHCHD10 OR CHCHD2 ARE NOT REQUIRED FOR HUMAN MOTOR NEURON DIFFERENTIATION IN VITRO BUT MODIFY SYNAPTIC TRANSCRIPTOMES

Mitochondrial intermembrane space proteins CHCHD2 and CHCHD10 have roles in diseases affecting motor neurons such as amyotrophic lateral sclerosis, spinal muscular atrophy and axonal neuropathy and in Parkinsons disease, and form a complex of unknown function. Here we address the importance of these two proteins in human motor neurons. We show that gene edited human induced pluripotent stem cells (iPSC) lacking either CHCHD2 or CHCHD10 are viable and can be differentiated into functional motor neurons that fire spontaneous and evoked action potentials. Knockout iPSC and motor neurons sustain mitochondrial ultrastructure and show reciprocal compensatory increases in CHCHD2 or CHCHD10. Knockout motor neurons have largely overlapping transcriptome profiles compared to isogenic control line, in particular for synaptic gene expression. Our results show that absence of CHCHD2 or CHCHD10 does not disrupt functionality, but induces similar modifications in human motor neurons. Thus pathogenic mechanisms may involve loss of synaptic function.

neuroscience↗