title: Impulse conduction increases mitochondrial transport in adult mammalian peripheral nerves in vivo.
abstract: Matching energy supply and demand is critical in the bioenergetic homeostasis of all cells. This is a special problem in neurons where high levels of energy expenditure may occur at sites remote from the cell body, given the remarkable length of axons and enormous variability of impulse activity over time. Positioning mitochondria at areas with high energy requirements is an essential solution to this problem, but it is not known how this is related to impulse conduction in vivo. Therefore, to study mitochondrial trafficking along resting and electrically active adult axons in vivo, confocal imaging of saphenous nerves in anaesthetised mice was combined with electrical and pharmacological stimulation of myelinated and unmyelinated axons, respectively. We show that low frequency activity induced by electrical stimulation significantly increases anterograde and retrograde mitochondrial traffic in comparison with silent axons. Higher frequency conduction within a physiological range (50 Hz) dramatically further increased anterograde, but not retrograde, mitochondrial traffic, by rapidly increasing the number of mobile mitochondria and gradually increasing their velocity. Similarly, topical application of capsaicin to skin innervated by the saphenous nerve increased mitochondrial traffic in both myelinated and unmyelinated axons. In addition, stationary mitochondria in axons conducting at higher frequency become shorter, thus supplying additional mitochondria to the trafficking population, presumably through enhanced fission. Mitochondria recruited to the mobile population do not accumulate near Nodes of Ranvier, but continue to travel anterogradely. This pattern of mitochondrial redistribution suggests that the peripheral terminals of sensory axons represent sites of particularly high metabolic demand during physiological high frequency conduction. As the majority of mitochondrial biogenesis occurs at the cell body, increased anterograde mitochondrial traffic may represent a mechanism that ensures a uniform increase in mitochondrial density along the length of axons during high impulse load, supporting the increased metabolic demand imposed by sustained conduction.
authors.affiliation: Department of Neuroinflammation, University College London, Institute of Neurology, London, United Kingdom.
authors.forename: Marija
authors.initials: M
authors.lastname: Sajic
authors.affiliation: Department of Neuroinflammation, University College London, Institute of Neurology, London, United Kingdom.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Mastrolia
authors.affiliation: Department of Neuroinflammation, University College London, Institute of Neurology, London, United Kingdom.
authors.forename: Chao Yu
authors.initials: CY
authors.lastname: Lee
authors.affiliation: Department of Neuroinflammation, University College London, Institute of Neurology, London, United Kingdom.
authors.forename: Diogo
authors.initials: D
authors.lastname: Trigo
authors.affiliation: Department of Neuroinflammation, University College London, Institute of Neurology, London, United Kingdom.
authors.forename: Mona
authors.initials: M
authors.lastname: Sadeghian
authors.affiliation: Department of Neuroinflammation, University College London, Institute of Neurology, London, United Kingdom.
authors.forename: Angelina J
authors.initials: AJ
authors.lastname: Mosley
authors.affiliation: Department of Neuroinflammation, University College London, Institute of Neurology, London, United Kingdom.
authors.forename: Norman A
authors.initials: NA
authors.lastname: Gregson
authors.affiliation: Department of Cell and Developmental Biology, University College London, London, United Kingdom.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Duchen
authors.affiliation: Department of Neuroinflammation, University College London, Institute of Neurology, London, United Kingdom.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Smith
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology; D004558:Electric Stimulation; D004734:Energy Metabolism / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron; D008928:Mitochondria / Q000502:physiology*; D009431:Neural Conduction / Q000502:physiology*; D010525:Peripheral Nerves / Q000502:physiology* / Q000648:ultrastructure