Abstract
Mitochondria are critical for the function and maintenance of myelinated axons notably through Adenosine triphosphate (ATP) production. A direct by-product of this ATP production is reactive oxygen species (ROS), which are highly deleterious for neurons. While ATP shortage and ROS levels increase are involved in several neurodegenerative diseases, it is still unclear whether the real-time dynamics of both ATP and ROS production in axonal mitochondria are altered by axonal or demyelinating neuropathies. To answer this question, we imaged and quantified mitochondrial ATP and hydrogen peroxide (H2O2) in resting or stimulated peripheral nerve myelinated axons in vivo, using genetically-encoded fluorescent probes, two-photon time-lapse and CARS imaging. We found that ATP and H2O2 productions are intrinsically higher in nodes of Ranvier even in resting conditions. Axonal firing increased both ATP and H2O2 productions but with different dynamics: ROS production peaked shortly and transiently after the stimulation while ATP production increased gradually for a longer period of time. In neuropathic MFN2R94Q mice, mimicking Charcot-Marie-Tooth 2A disease, defective mitochondria failed to upregulate ATP production following axonal activity. However, elevated H2O2 production was largely sustained. Finally, inducing demyelination with lysophosphatidylcholine resulted in a reduced level of ATP while H2O2 level soared. Taken together, our results suggest that ATP and ROS productions are decoupled under neuropathic conditions, which may compromise axonal function and integrity.
Highlights
While the nervous system, and the brain in particular, represents around 2% of the body mass, it consumes up to 20% of the glucose we mobilize every day [37]
This probe consists of the cyan fluorescent protein (CFP) mseCFP, the yellow fluorescent protein (YFP) variant monomeric Venus, both linked at the ε-subunit of the Bacillus subtilis FoF1-Adenosine triphosphate (ATP) synthase
ATP and Hydrogen peroxide (H2O2) production are altered in CMT2A neuropathic mice We recently showed that MFN2R94Q mice, a model for CMT2A disease [13] where mitofusin 2 (MFN2) is defective, displayed altered mitochondria motility and clustering in peripheral nerve axons [9]
Summary
The brain in particular, represents around 2% of the body mass, it consumes up to 20% of the glucose we mobilize every day [37]. This high energy expenditure in the nervous system is firstly due to the synaptic activity that requires high amounts of ATP [37]. Mitochondria appear to be the main source of cellular ATP and these organelles are abundant in CNS [24, 48] and PNS [81] axons. A well-accepted idea is that axonal AP activity
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