Intermitochondrial signaling regulates the uniform distribution of stationary mitochondria in axons

Abstract

In the central nervous system, many neurons develop axonal arbors that are crucial for information processing. Previous studies have demonstrated that premature axons contain motile and stationary mitochondria, and their balance is important for axonal arborization. However, the mechanisms by which neurons determine the positions of stationary mitochondria as well as their turnover remain to be elucidated. In this study, we investigated the regulation of spatiotemporal group dynamics of stationary mitochondria. We observed that the distribution of stationary mitochondrial spots along the unmyelinated and nonsynaptic axons is not random but rather relatively uniform both in vitro and in vivo. Intriguingly, whereas the positions of each mitochondrial spot changed over time, the overall distribution remained uniform. In addition, local inactivation of mitochondria inhibited the translocation of mitochondrial spots in adjacent axonal regions, suggesting that functional mitochondria enhance the motility of neighboring mitochondria. Furthermore, we showed that the ATP concentration was relatively high around mitochondria, and treating axons with phosphocreatine, which supplies ATP, reduced the immobile mitochondria induced by local mitochondrial inhibition. These observations indicate that intermitochondrial interactions, mediated by ATP signaling, control the uniform distribution of axonal mitochondria. The present study reveals a novel cellular system that collectively regulates stationary mitochondria in axons.

3-nitrotyrosine shortens axons of a non-dopaminergic neuron by inhibiting mitochondrial motility

“…By labeling with MitoTracker, both motile and stationary mitochondria were observed in axons of control CGNs at 3 DIV (Fig. 4A), consistent with the previous report (Matsumoto et al, 2022). In CGN axons treated with 3-NT for 8 hours, mitochondria tended to remain stationary during observation (Fig.…”

“…Animals had access to food and water ad libitum. CGNs were prepared from Jcl:ICR mice (CLEA Japan, Tokyo, Japan) at postnatal days 4 to 6 as described previously (Kubota et al, 2013, Matsumoto et al, 2022. Following decapitation, isolated cerebellar were digested with trypsin (10 mg/ml)-DNase (200 units/ml) (TRL, DP, Worthington, Lakewood, NJ) solution.…”

Under Pressure: A Microfluidic Chip for Prolonged, Anesthetic-Free Imaging of Neuronal Mitostasis inCaenorhabditis elegans

“…C. elegans develops rapidly compared with other animals, reaching adulthood in 3 d, and the PLM axon elongates at a rate of ∼10 μm/h, as measured by Mondal et al (2021) . Consistent with reports on cell culture and explants ( Miller and Sheetz, 2004 ; Lamoureux et al, 2010 ; Matsumoto et al, 2020 ), Mondal et al (2021) observed that new mitochondria were added to the developing neuron between pairs of stationary mitochondria. These new additions occur at a rate of ∼0.6 mitochondria/h, further highlighting the need for prolonged imaging sessions to observe a sufficient number of events.…”

Tracking Mitochondrial Density and Positioning along a Growing Neuronal Process in IndividualC. elegansNeuron Using a Long-Term Growth and Imaging Microfluidic Device

“…New mitochondrion addition during growth and axon stretching has been shown to occur between adjacent pairs of stationary mitochondria ( Miller and Sheetz, 2004 ; Lamoureux et al, 2010 ; Misko et al, 2012 ; Matsumoto et al, 2020 ). Our data are consistent with prior observations where we see a uniform distribution of mitochondria, proportionate growth of the neuron, and addition of mitochondria occurring anywhere along the process between two stationary mitochondria ( Fig.…”