Normally, cells recycle mitochondria by breaking them down in lysosomes in a process called mitophagy. However, new work suggests that certain neurons delegate the cleanup to nearby glia. Scientists led by Nicholas Marsh-Armstrong, The Johns Hopkins University School of Medicine, Baltimore, and Mark Ellisman, University of California, San Diego, found that the axons of retinal ganglion cells expel bundles containing mitochondria into the surrounding milieu. Neighboring astrocytes then appear to gobble them up.
“This is a very interesting discovery, as it describes a completely novel process through which neurons can get rid of their mitochondria,” Ben Barres, Stanford University School of Medicine, California, wrote to Alzforum in an email. Barres was not involved in the study, which appeared online June 16 in the Proceedings of the National Academy of Sciences.
Previously, Marsh-Armstrong and colleagues noticed protrusions sprouting from the axons of healthy retinal ganglion cells in the optic nerve head (ONH) of normal mice. These were engulfed by astrocytes (see Nguyen et al., 2011). In the current study, they used electron microscopy to see what was inside these bundles.
In two mice, one three months old and the other nine months old, the clumps contained full and fragmented mitochondria, complete with their characteristic inner membrane folds, or cristae. Each package contained about 30 mitochondria. The axons that released them seemed healthy. The researchers also found microtubules and unidentified flotsam inside the bundles, suggesting the axons disposed of additional components this way.
To confirm the organelles came from neurons, first author Chung-ha Davis and colleagues introduced a fluorescent mitochondrial reporter into the retinal neurons of 29 mice. Many labeled mitochondria ended up in astrocytes at the optic nerve head. Almost five times more mitochondria were broken down there than were degraded inside neuron bodies.
Given that the optic nerve head is a specialized structure, the researchers wondered whether this phenomenon, which they termed “transmitophagy,” occurred elsewhere. When they looked near serotonergic neurons of the cerebral cortex, they found some evidence of it, hinting that transmitophagy could occur in other areas of the nervous system, the authors wrote.
While it’s unclear why neurons might use transmitophagy, the researchers speculate that it helps long axons eliminate garbage by giving it a more efficient disposal system than transporting it all back to the soma, where the neuronal lysosomes reside. Neurons overwhelmed by their mitochondrial load or under stress might also rely on this mechanism, they suggested. This expulsion of axon components could explain how material typically found inside neurons ends up outside, for example proteins linked to neurodegenerative disease, such as Aβ and α-synuclein, Marsh-Armstrong told Alzforum. He speculated that dysfunctional glial processing could contribute to extracellular build-up of toxic proteins. He said his group next plans to check whether this process malfunctions in animal models of glaucoma. This eye disease causes loss of retinal ganglion cells and scientists hypothesize that mitochondrial dysfunction may be involved (see Kong et al., 2009). The researchers will also check to see where else this process takes place in the central nervous system.
Outside experts were intrigued by the finding (see comments below). “It’s a fundamental piece of physiology that wasn’t generally recognized before,” said Russell Swerdlow, University of Kansas, Kansas City. He noted that the study could have implications for neuroinflammation. Mitochondria retain some of their prokaryotic roots, he explained, so if a breakdown in transmitophagy abandons mitochondria outside the cell, the immune system might interpret them as foreign and mount a response. In the big picture, the results contribute to the evolving notion that astrocytes have important intricate physiological relationships with neurons, he said.—Gwyneth Dickey Zakaib
- Nguyen JV, Soto I, Kim KY, Bushong EA, Oglesby E, Valiente-Soriano FJ, Yang Z, Davis CH, Bedont JL, Son JL, Wei JO, Buchman VL, Zack DJ, Vidal-Sanz M, Ellisman MH, Marsh-Armstrong N. Myelination transition zone astrocytes are constitutively phagocytic and have synuclein dependent reactivity in glaucoma. Proc Natl Acad Sci U S A. 2011 Jan 18;108(3):1176-81. PubMed.
- Kong GY, Van Bergen NJ, Trounce IA, Crowston JG. Mitochondrial dysfunction and glaucoma. J Glaucoma. 2009 Feb;18(2):93-100. PubMed.