Research Highlights
Astrocytes Devour Neuronal Mitochondria in a Newly Documented Process Called Transmitophagy
June 2014 La Jolla
Scientific canon long held that when the tiny energy producers within cells, called mitochondria, become damaged or dysfunctional, these tiny organelles are degraded and recycled within the cell that produced them. But a paper appearing in the Proceedings of the National Academy of Sciences (PNAS) from The Johns Hopkins University and NCMIR scientists now shows that, instead, particularly in the long axons of the brain’s nerve cells, damaged mitochondria are transferred to nearby glial cells for elimination. This process, in effect, outsources a substantial portion of the neurons’ housekeeping.
A research team made up of Dr. Nicholas Marsh-Armstrong’s laboratory at The Johns Hopkins University (JHU), the Kennedy Krieger Institute, and NCMIR scientists recently reported this new paradigm. It was revealed from careful study of the fate of mitochondria in the axons of retinal ganglion cells in mice. Mice are close enough genetically to humans that they are often used to “model” disease to better understand underlying mechanisms and explore possible treatment strategies for diseases affecting people, such as glaucoma.
Retinal ganglion neurons are a type of nerve cell that transmits visual information from the eye to the brain. The research team determined that large numbers of damaged mitochondria in retinal ganglion cells were shed at a site right behind the eye in an area called the optic nerve head where ganglion neuron axons exit the eye to form the optic nerve, carrying signals from the eye to the brain. The transferred pieces of mitochondria were then absorbed and broken down inside organelles, called lysosomes, of these adjacent, specialized glial cells.
This work is the first demonstration of a process, now called transmitophagy, used by nerve axons of the visual system. But evidence suggests this outsourcing capacity may be fundamental and exist in other regions of the brain. Hence, this result, with its immediate implications for biomedical research on eye disease, is likely to have a profound impact on studies on other topics related to the brain in general, most particularly age-associated neurodegenerative processes such as those occurring in Parkinson’s and Alzheimer’s disease.
From the results of his work supported by a Glaucoma Research Foundation catalyst program, Marsh-Armstrong believed that the early events could extend back into the optic nerve through the entire initial region, all the way to where a special form of glia started the job of providing insulation (fatty myelin layers) to help the electric signal propagate rapidly to the brain. This optic nerve head (ONH) zone, which is not covered with myelin, appeared to release materials manufactured in the ganglion cell when the locations of some proteins were imaged in a mouse model of glaucoma.
At the time, the glaucoma research community was beginning to recognize data pointing to a specialized type of glia, the astrocyte, as having a role in activities associated with inflammation of the ONH in glaucoma. The International Retina Research Foundation, the Lasker Foundation, and the Howard Hughes Medical Institute brought together 50 scientists from around the U.S. to discuss possible new strategies and collaborations that would accelerate progress resulting from glaucoma research. Dr. Marsh-Armstrong attended this meeting where he met Mark Ellisman. Ellisman, a professor of Neuroscience and Bioengineering at UCSD and NCMIR director, who is an expert on the structure and function of the astrocyte. Some 10 years ago, Ellisman and his team, using high-resolution imaging technology, determined that the astrocyte, which had been thought to be a simple, star-shaped glial cell, was actually much more complicated. In fact, some 85% of the shape of the cell had been missed altogether.
During the three-day meeting, Ellisman and Marsh-Armstrong discussed how to apply recently developed imaging technologies to study, in more detail and higher resolution, a process that Marsh-Armstrong had observed related to the release of substances behind the eye that appeared more extreme in glaucoma. Marsh-Armstrong and Ellisman realized that new approaches under development at NCMIR might address questions Marsh-Armstrong had articulated. NCMIR scientists applied a new high-resolution, volume-imaging strategy that uses a scanning electron microscope, called serial block face scanning electron microscopy, in a highly automated manner to reconstruct large portions of the ONH in a mouse model to determine more precisely where the first signs of glaucoma appear.
Before they began working with samples from the model, though, Ellisman spotted what he interpreted were static images of transfer between the retinal ganglion neuron axons and associated astrocytes, remarking to his colleague that it looked like they were passing off parts of mitochondria. The two researchers and their respective teams published a scientific paper in 2011 in PNAS showing the location of the transfer of material—without identifying it specifically as axonal mitochondria. In this new study, JHU and NCMIR scientists unequivocally show that surprisingly large proportions of retinal ganglion cell axonal mitochondria are normally degraded by the astrocytes of the ONH. This transcellular degradation of mitochondria, or transmitophagy, also occurs in the Central Nervous System, because structurally similar accumulations of degrading mitochondria are also found along projections from neuron cell bodies in superficial layers of the cerebral cortex in the brain. This finding calls into question the dogma that a cell necessarily degrades its own organelles.
Funding for this research came, in part, from the National Institutes of Health (grants R01 EY022680 and R01 EY019960), the International Retina Research Foundation, the Glaucoma Research Foundation, the Melza M. and Frank Theodore Barr Foundation, the National Center for Research Resources (grant 5P41RR004050), the National Institute on Drug Abuse Human Brain Project (grant DA016602), the National Institute of General Medical Sciences (grants 5R01GM82949 and 5P41GM103412-25), an NIGMS training grant (grant 5T32GM07814), and the National Science Foundation (grant DGE-1232825).
Citation: Chung-ha O. Davis, Keun-Young Kim, Eric A. Bushong, Elizabeth A. Mills, Daniela Boassa, Tiffany Shih, Mira Kinebuchi, Sebastien Phan, Yi Zhou, Nathan A. Bihlmeyer, Judy V. Nguyen, Yunju Jin, Mark H. Ellisman, and Nicholas Marsh-Armstrong, Transcellular degradation of axonal mitochondria, Early Edition of the Proceedings of the National Academy of Sciences of the United States of America, July 17, 2014, www.pnas.org/cgi/doi/10.1073/pnas.1404651111.