Calcium Release from Intra-Axonal Endoplasmic Reticulum Leads to Axon Degeneration through Mitochondrial Dysfunction

• DOI: 10.1523/jneurosci.4784-13.2014
• Publication Date: 2014-05-21T17:05:00Z
• Authors: Rosario Villegas; Nicolas W. Martinez; Jorge Lillo; Phillipe Pihan; Diego Hernandez; Jeffery L. Twiss; Felipe A. Court
• Keywords: Male; Mitochondrial Diseases; 610; Endoplasmic Reticulum; Retículo endoplásmico; Rats, Sprague-Dawley; Mice; 03 medical and health sciences; Imaging, Three-Dimensional; Organ Culture Techniques; Microscopy, Electron, Transmission; Pregnancy; Ganglia, Spinal; Degeneración neuronal; Animals; Membrane Potential, Mitochondrial; 0303 health sciences; Embryo, Mammalian; Sciatic Nerve; Axons; Rats; Mice, Inbred C57BL; Ganglios espinales; Calcium; Female; Medicina y salud; Axones; Reactive Oxygen Species

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 IP3channels activates the mitochondrial permeability transition pore and contributes to axonal degeneration triggered by both mechanical and toxic insults inex vivoandin vitromouse 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.