Self-renewal of neuronal mitochondria through asymmetric division
Posted on: 6 February 2026
Preprint posted on 18 December 2025
Neurons contain “hotspots” for mitochondrial biogenesis at distal branch points
Selected by Lorena Olifiers
Categories: cell biology, neuroscience
Significance of this study
Mitochondria seem to live their own inner lives inside neurons. The age of proteomics and high-resolution microscopy methods now allow us to ask bigger questions as to how mitochondrial populations within the neuron specialize, how they can supply the hungry neuron for a human lifetime, and in what cases this goes wrong. Given this organelle’s involvement with many neurodevelopmental, neurodegenerative and even psychiatric conditions, understanding mitochondrial homeostasis could be key to devising new therapies for a range of different diseases. This preprint counteracts the dogma that mitochondrial biogenesis is exclusive to the cell body and brings us a big step closer to understanding these organelles’ inner workings.
Background
Despite being famously coined the “powerhouse of the cell”, the mitochondria are specialized for many other functions beyond ATP production, such as calcium buffering, fatty acid breakdown, amino acid synthesis and cell death. Several of these functions are vital for a needy cell such as neuron, and its complex architecture indicates the mitochondria must be specialized depending on the neuronal compartment in which it operates. How are these mitochondria kept “fresh” in long-projection cells such as afferent sensory neurons? Tejashree P. Waingankar & colleagues discovered a crucial piece of this puzzle: the possibility of mitochondrial replenishment far away from the cell body.
Key findings
mtDNA levels exhibit a gradient within neurites and are highly abundant at branch point mitochondria
In order to divide, mitochondria must replicate their own DNA (mtDNA), containing 13 components of the electron transport chain and some of its exclusive translational machinery. In accordance with a previous preprint (Hirabayashi, 2024), the authors found most mitochondria in the neurite lacked nucleoids- packages of mtDNA- in comparison to the soma. In stationary mitochondria, they found a gradient of mtDNA distribution: from lowest at the neurite portions closer to the nucleus, to highest at collateral branching points, but somehow most moving mitochondria seemed to be void of mtDNA. Interestingly, nucleoids were highly enriched at branch points of neurons and co-localized with the enriched TFAM (important for mtDNA structural and replication purposes), indicating these locations serve as “hotspots” for mtDNA replication and regulation of mitochondrial biogenesis.
Branch point mitochondria have higher membrane potential and ATP synthesis levels, and are equipped with tools for mitochondrial biogenesis both in vitro and in vivo
A characterization of the membrane potential of mitochondria using TMRE dye revealed that neurite mitochondria had lower membrane potential, and thus overall lower “respiration potential” compared to stationary branch point mitochondria. It also proved that for both groups (branch point vs. rest of neurite) the maintenance of membrane potential is complex-I dependent. The use of another dye, Biotracker ATP, indicated the mitochondria at branch points are also more energetically functional.
In order to investigate the potential for biogenesis at these distal hotspots, the authors used click-biochemistry to label new DNA- or RNA-chains and found both mtDNA replication and RNA transcription to be taking place at these branch points.
At this point, one key question remained: are only transcripts originating from the mtDNA being translated at this location, or are nuclear transcripts also involved? An RNA-fish approach, combined with a puromycylation labeling experiment, revealed the branch point to be a site of active translation of both mitochondrial and nuclear transcripts. These findings highlight that both nuclear and mitochondrial genes somehow coordinate distal mitochondrial biogenesis at long distances from the nucleus.
A partitioning mechanism of nucleoid-devoid motile mitochondria by a biogenesis-dedicated stationary “mother” mitochondrion
Interested in potential mitochondrial dynamics at the distal portion of the neuron, the authors combined their neuronal culture with a powerful tool: the photoconvertible protein Dendra2, which shifts its emission spectrum from green to red upon UV induction and allows for the subdivision of mitochondrial populations for imaging. This approach revealed the rarity of fusion and fission events either in the neurite or at the branch point, indicating that moving (i.e ‘green’) and stationary (photoconverted ‘red’) mitochondria do not often fuse and mix their matrix contents.
In the stationary mitochondria at the branch point, however, mitochondrial division seemed to be abundant. In 91% of cases, a motile daughter mitochondrion was born which lacked mtDNA and had lower Biotracker ATP fluorescence intensity. Interestingly, further quantification revealed that these nascent genome-less mitochondria were much more motile than those carrying mtDNA nucleoids. As for the mother mitochondrion, an increase in both TMRE intensity and Biotracker-ATP fluorescence intensity after asymmetric division suggests this mother mitochondrion undergoes a sort of “rejuvenation”.
Conclusion
Clues that mitochondria undergo biogenesis far away from the soma have surfaced over the last decade. This preprint by Waingankar and team defends the idea that mitochondria are semi-autonomous in their operations within the neuron. They are equipped with both their own tools (mtDNA) and nuclear-derived stocks of mRNA which they “hoard” to allow themselves to undergo division at dedicated stations within the neurite, such as the branch points. This study opens many avenues of further research, such as the role of mtDNA in the distal portions of the neuron, the possible molecular mechanisms behind sensing mitochondrial matrix content, and how the maintenance of this tiny plasmid inside mitochondria may be involved in disease progression.
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