Calcium release from intra-axonal endoplasmic reticulum leads to axon degeneration through mitochondrial dysfunction.
Axonal degeneration represents an early pathological event in neurodegeneration, constituting an important target for neuroprotection. Regardless of the initial injury, which could be toxic, mechanical, metabolic, or genetic, degeneration of axons shares a common mechanism involving mitochondrial dysfunction and production of reactive oxygen species. Critical steps in this degenerative process are still unknown. Here we show that calcium release from the axonal endoplasmic reticulum (ER) through ryanodine and IP3 channels activates the mitochondrial permeability transition pore and contributes to axonal degeneration triggered by both mechanical and toxic insults in ex vivo and in vitro mouse and rat model systems. These data reveal a critical and early ER-dependent step during axonal degeneration, providing novel targets for axonal protection in neurodegenerative conditions.
Millennium Nucleus for Regenerative Biology, Department of Physiology, Faculty of Biology, Pontificia Universidad Catolica de Chile, Santiago 8331150, Chile.
Rosario
R
Villegas
Millennium Nucleus for Regenerative Biology, Department of Physiology, Faculty of Biology, Pontificia Universidad Catolica de Chile, Santiago 8331150, Chile.
Nicolas W
NW
Martinez
Millennium Nucleus for Regenerative Biology, Department of Physiology, Faculty of Biology, Pontificia Universidad Catolica de Chile, Santiago 8331150, Chile.
Jorge
J
Lillo
Millennium Nucleus for Regenerative Biology, Department of Physiology, Faculty of Biology, Pontificia Universidad Catolica de Chile, Santiago 8331150, Chile.
Phillipe
P
Pihan
Millennium Nucleus for Regenerative Biology, Department of Physiology, Faculty of Biology, Pontificia Universidad Catolica de Chile, Santiago 8331150, Chile.
Diego
D
Hernandez
Department of Biological Sciences, University of South Carolina, Columbia, South Carolina 20208, and.
Jeffery L
JL
Twiss
Millennium Nucleus for Regenerative Biology, Department of Physiology, Faculty of Biology, Pontificia Universidad Catolica de Chile, Santiago 8331150, Chile, NeuroUnion Biomedical Foundation, Santiago 7630614, Chile fcourt@bio.puc.cl court.felipe@gmail.com.
Felipe A
FA
Court
D000818:Animals; D001369:Axons / Q000648:ultrastructure*; D002118:Calcium / Q000378:metabolism*; D004622:Embryo, Mammalian; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005727:Ganglia, Spinal / Q000378:metabolism / Q000648:ultrastructure; D021621:Imaging, Three-Dimensional; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D028361:Mitochondrial Diseases / Q000473:pathology / Q000503:physiopathology*; D009924:Organ Culture Techniques; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D012584:Sciatic Nerve / Q000648:ultrastructure
D017382:Reactive Oxygen Species; D002118:Calcium
axon degeneration; endoplasmic reticulum; mPTP; mitochondria; neurodegeneration