Getting Rid of Old Mitochondria
Some neurons turn to neighbors to help take out the trash
It’s broadly assumed that cells degrade and recycle their own old or damaged organelles, but researchers at University of California, San Diego School of Medicine, The Johns Hopkins University School of Medicine and Kennedy Krieger Institute have discovered that some neurons transfer unwanted mitochondria – the tiny power plants inside cells – to supporting glial cells called astrocytes for disposal.
The findings, published in the June 17 online Early Edition of PNAS, suggest some basic biology may need revising, but they also have potential implications for improving the understanding and treatment of many neurodegenerative and metabolic disorders.
“It does call into question the conventional assumption that cells necessarily degrade their own organelles. We don’t yet know how generalized this process is throughout the brain, but our work suggests it’s probably widespread,” said Mark H. Ellisman, PhD, Distinguished Professor of Neurosciences, director of the National Center for Microscopy and Imaging Research (NCMIR) at UC San Diego and co-senior author of the study with Nicholas Marsh-Armstrong, PhD, in the Department of Neuroscience at Johns Hopkins University and the Hugo W. Moser Research Institute at Kennedy Krieger Institute in Baltimore.
From idea to published discovery: the whole story
Scientific canon long held that when the tiny energy producers within cells, called mitochondria, became damaged or dysfunctional these tiny organelles were degraded and recycled within the cell that produced them. But recent research shows that damaged mitochondria, particularly in the long axons of the brain’s nerve cells, are instead 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 scientists from the University of California, San Diego School of Medicine and Johns Hopkins University (JHU) School of Medicine 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 (ONH), 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 by lysosomes inside adjacent, specialized glial cells. This surprising result upends the assumption that a cell necessarily degrades its own organelles, particularly its own mitochondria.
The work is the first demonstration of a process, dubbed 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.
Behind the findings, however, is a another story of how the discovery came to be, one that reveals the critical roles played by diverse research-promoting mechanisms used by foundations and the federal government to cultivate and catalyze interdisciplinary, collaborative approaches needed to address hard questions and produce new understanding of complex biomedical questions.
Scientific discoveries often seem to be reported as isolated, discrete conclusions: Scientist X conducted research Y and obtained conclusion Z. This structure implies a simple linear progression. End of story. Though the impact of these discoveries is often felt, the process that produced these discoveries, like hard scientific questions themselves, tends to be insufficiently understood.
But modern science is complicated and far from linear. It often involves years of traversing switchbacks on the scientific trail; intense technology development and application with successes and failures; and scientific personalities, with different talents and roles, scattered geographically. All of this is true of the story at hand.
To illustrate how such scientific discoveries can be realized, let’s pick up the transmitophagy story mid-stream: Nicholas Marsh-Armstrong, a young Harvard-trained molecular neurobiologist chose to focus his research program on glaucoma, a devastating but common scourge that progressively robs the elderly of sight. His creativity and penchant for studying hard problems using relevant, simple systems in frog or mouse models of disease had been noticed by the Glaucoma Research Foundation and National Institutes of Health, which provided him with support to study a specialized region behind the eye for clues as to the first changes that might be harbingers of glaucoma.
Like others before him, he sought answers to what cellular and molecular events initiated the process that ultimately leads to the breakdown of the nerve axons belonging to the retinal ganglion cells which, once lost, lead to glaucoma.
Based on work supported by a Glaucoma Research Foundation catalyst program, Marsh-Armstrong believed the early events might 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 – the ONH.
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. Growing suspicion that there might be more to this story helped motivate a series of small meetings, sponsored by The International Retina Research Foundation, the Lasker Foundation, and the Howard Hughes Medical Institute, which brought together 50 scientists from around the United States to discuss possible new strategies and collaborations that would accelerate progress resulting from glaucoma research.
Marsh-Armstrong attended this meeting where he met Ellisman, a professor of neuroscience and bioengineering at UC San Diego and director of the National Center for Microscopy and Imaging Research (NCMIR). Ellisman specializes in advanced imaging technology development and applications. He is also an expert on the structure and function of the astrocyte.
A decade earlier, Ellisman and colleagues, 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 percent of the cell’s shape had been previously overlooked.
Scientists had been seeing the forest but missing the trees or in this case, the leaves. Ellisman’s team also determined that rather than being intertwined, the branches of astrocytes occupied their own unique spaces or “tiles” in the brain. He was invited to the meeting because the glaucoma research community was interested in understanding the role of astrocytes in the ONH more fully, and the imaging strategies of his group at NCMIR were thought to be a key to addressing this knowledge gap.
During the three-day meeting, Ellisman and Marsh-Armstrong discussed how to apply recently developed imaging technologies to study. In particularly, Marsh-Armstrong wanted to look at the released substances behind the eye in greater detail. The International Retina Research Foundation offered small short-term grants to support creative ideas that emerged from the meeting. Marsh-Armstrong and Ellisman applied and received support. Their plan was for Ellisman’s group to apply a new high-resolution, volume-imaging strategy that uses a scanning electron microscope 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, however, 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.
At the time, these observations were kept muted. They were very controversial. More analysis and careful assessment would be required to determine if this surprising observation and predictive interpretation would hold up under scrutiny from the community.
The two researchers and their respective teams wrote up this preliminary study and published one scientific paper showing the location of the transfer of material—without identifying it specifically as axonal mitochondria.
The preliminary results proved sufficient to support a successful request for a small grant from the NIH’s National Eye Institute. From that point, it took two to three years and many creative strategies from both labs to gather sufficient data to determine if their interpretation of static images, representing the dynamic transfer of mitochondria, was correct. They reasoned that this would be required before they could publish the work in a peer-reviewed journal.
This is an instructive tale for many reasons. First, it demonstrates a relationship between philanthropic foundations and federal funding agencies in supporting the continuum of the scientific enterprise. Both types of organizations sponsor exclusive topical meetings and invite experts across a range of disciplines to discuss and identify the frontiers—and the intersection of those frontiers—where science can be advanced. The foundation provides seed funding to stimulate new research directions. This seed funding enables scientists to conduct research, demonstrate preliminary progress (proof of concept) on a topic and get some papers published, all of which serves as the basis for pursuing a grant from a federal funding agency for a more ambitious, longer-range project. This continuum can support researchers at both earlier and later stages of their scientific thinking.
Second, and more importantly, it shows the potential for catalysis when researchers, looking at a problem from different points of view, collaborate. In this case, high-performance computing (HPC), communications and imaging capabilities were brought to bear on an interesting scientific question that, arguably, couldn’t have been addressed as efficiently otherwise. This is an important example of the value of advanced technology resources set up by NIH, such as NCMIR and other research resources, and how they apply their open-access, state-of-the-art technologies and staff expertise to answer hard questions, materially advance scientific understanding, and benefit society as a result.
This project, transcontinental in nature, was made possible by continuing large federal investments (primarily by NIH and the National Science Foundation) in cyberinfrastructure: HPC, high-bandwidth telecommunications networks, infrastructure to support large data (acquisition, storage, analysis, and curation), high-resolution imaging systems, access gateways, and related digital technology and development.
Today researchers, regardless of location, can choose their collaborators more selectively than ever, which leads to creation of large teams working across disciplinary boundaries, which, common wisdom holds, is where the most innovative work takes place.