Edited by Ben A. Barres, Stanford University School of Medicine, Stanford, CA, and approved May 22, 2014 (received for review March 12, 2014)
Mitochondria are organelles that perform many essential functions, including providing the energy to cells. Cells remove damaged mitochondria through a process called mitophagy. Mitophagy is considered a subset of a process called autophagy, by which damaged organelles are enwrapped and delivered to lysosomes for degradation. Implicit in the categorization of mitophagy as a subset of autophagy, which means “self-eating,” is the assumption that a cell degrades its own mitochondria. However, we show here that in a location called the optic nerve head, large numbers of mitochondria are shed from neurons to be degraded by the lysosomes of adjoining glial cells. This finding calls into question the assumption that a cell necessarily degrades its own organelles.
It is generally accepted that healthy cells degrade their own mitochondria. Here, we report that retinal ganglion cell axons of WT mice shed mitochondria at the optic nerve head (ONH), and that these mitochondria are internalized and degraded by adjacent astrocytes. EM demonstrates that mitochondria are shed through formation of large protrusions that originate from otherwise healthy axons. A virally introduced tandem fluorophore protein reporter of acidified mitochondria reveals that acidified axonal mitochondria originating from the retinal ganglion cell are associated with lysosomes within columns of astrocytes in the ONH. According to this reporter, a greater proportion of retinal ganglion cell mitochondria are degraded at the ONH than in the ganglion cell soma. Consistently, analyses of degrading DNA reveal extensive mtDNA degradation within the optic nerve astrocytes, some of which comes from retinal ganglion cell axons. Together, these results demonstrate 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, likely occurs elsewhere in the CNS, because structurally similar accumulations of degrading mitochondria are also found along neurites in superficial layers of the cerebral cortex. Thus, the general assumption that neurons or other cells necessarily degrade their own mitochondria should be reconsidered.
↵1M.H.E. and N.M.-A. contributed equally to this work.
Author contributions: M.H.E. and N.M.-A. designed research; C.-h.O.D., K.-Y.K., E.A.B., E.A.M., D.B., T.S., M.K., S.P., Y.Z., N.A.B., J.V.N., Y.J., and N.M.-A. performed research; C.-h.O.D., K.-Y.K., E.A.B., E.A.M., D.B., M.H.E., and N.M.-A. analyzed data; and C.-h.O.D. and N.M.-A. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
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