. Transcellular degradation of axonal mitochondria. Proc Natl Acad Sci U S A. 2014 Jul 1;111(26):9633-8. Epub 2014 Jun 16 PubMed.


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  1. Davis and coworkers have uncovered an exciting neurobiological phenomenon whereby mitochondria in retinal ganglion cells are "shed" and taken up by nearby astrocytes. The authors are dubbing this "transmitophagy," or transcellular degradation of mitochondria. As duly pointed out by the authors, this exciting new finding likely occurs in other CNS regions. While the authors have focused in this report on physiological transmitophagy, their results nonetheless beg the question of what happens vis-a-vis pathological CNS states like Alzheimer’s disease.

    View all comments by Terrence Town
  2. This is an exciting new finding on a pathway of neuronal mitochondrial degradation and clearance. The authors provide convincing data showing a process through which the axonal mitochondria can be shed through evulsion and then be phagocytosed by adjacent astrocytes. This is a new pathway for maintenance of mitochondrial health in addition to mitochondrial fission, fusion, and mitophagy, and it is possibly unique for neuronal axons. This phenomenon is found in a healthy mouse optic nerve head after intravitreal injection of a reporter gene. The optic nerve head is a region crowded with axons without myelination and it is very vulnerable to increased tissue pressure. Therefore, it is not clear whether this is a normal phenomenon or this is related to early axonal injury. Interestingly, “transmitophagy” was also found in the cerebral cortex, although much less frequently. There is a possibility that microglia besides astrocytes might also play a role in clearance of unhealthy mitochondria within the nervous system.

    Further study is necessary to elucidate the signaling and cellular pathways involved in the transcellular mitophagy, which might help us understand how axons maintain their health through restoration of mitochondrial integrity and the pathogenesis of various neurological disorders such as neurodegenerative disorders. 

    View all comments by Shirley ShiDu Yan
  3. I think this is a very interesting discovery as it describes a completely novel process, transmitophagy, through which neurons can get rid of their mitochondria. Recent studies, including our own, have indicated that astrocytes are highly phagocytic cells, so it will be interesting to see if specific astrocyte phagocytic pathways are mediating this transmitophagy. It will also be extremely interesting to know if defects in this process could lead to neurodegenerative disease. For instance, when the retinal pigment cells, which are phagocytic, are defective in their ability to eat the "shed" used up portions of photoreceptor outer segments, a retinal degenerative disorder results.

    View all comments by Ben Barres
  4. This is truly an exciting paper with an elegant demonstration of extrusion of mitochondria and potentially other axonal components into the extracellular milieu and reuptake by glia. This process, named transmitophagy by the authors, has also been described previously by three-dimensional electron microscopy in aged rhesus monkeys (Fiala et al., 2007) and the hippocampi of aged wild-type mice (Doehner et al., 2012).

    Interestingly, in wild-type mice that were prenatally exposed to a viral–like challenge that resulted in AD-like changes in aged animals (Krstic et al., 2012), the number of these transmitophagy events increased, and each consisted of higher mitochondria density (Doehner et al., 2012).

    In line with the Davis et al.’s hypothesis that transmitophagy may be an efficient garbage disposal system of long-projection neurons, we proposed recently that brain injury (e.g., brain and axonal damage, chronic neuroinflammation, oxidative stress, etc.) might impair the transmitophagy process and result in enlargement and concomitant disruption of these axonal buddings (Krstic and Knuesel, 2013). This phenomenon was, in fact, described in a postmortem tracing study in human AD brain slices (Xiao et al., 2011).

    Altogether, the findings presented here provide a first functional insight into a putative protective axonal mechanism that has been described earlier and has served as basis for a novel cellular mechanism of senile plaque and neurofibrillary tangle formation in late-onset Alzheimer’s disease. (Krstic and Knuesel, 2013).

    One could go even further and speculate that the fibrillary amyloid plaques might actually represent a hydrophobic seal of a source of ECM-floating mitochondria and hence be an aide de camp in the neuronal battle against neurodegeneration. It would not be surprising, therefore, to find a regulatory role of APP in the transmitophagy process. (Krstic and Knuesel, 2013).


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    . The origin and development of plaques and phosphorylated tau are associated with axonopathy in Alzheimer's disease. Neurosci Bull. 2011 Oct;27(5):287-99. PubMed.

    . The airbag problem-a potential culprit for bench-to-bedside translational efforts: relevance for Alzheimer's disease. Acta Neuropathol Commun. 2013 Sep 23;1(1):62. PubMed.

    View all comments by Dimitrije Krstic

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