INSIGHTS | PERSPECTIVES
386 25 JULY 2014 • VOL 345 ISSUE 6195
sciencemag.org SCIENCE
from the axon to the cell body (10). How or
where mitophagy is induced in the axon, or
precisely how many mitochondria are eliminated by autophagy versus alternate mechanisms (axonal or otherwise), is not clear (11).
A study of retinal ganglion cells at the optic nerve head in a mouse revealed that membrane-bound vesicles that were shed from
their axons were internalized by surrounding
astrocytes (12). Davis et al. further analyzed
this shedding event. Using scanning electron
microscopy and cell-specific labeling, they
identified mitochondria as one of the major
constituents of the shed axonal evulsions.
A clear continuum of events was observed
whereby mitochondria clustered in axons
near sites of astrocyte membranes, evulsions
from axons were filled with mitochondria,
and shed evulsions were internalized by astrocytes. The authors further determined
that the mitochondria-rich evulsions were
degraded in astrocytes, as the organelles colocalized with lysosomal markers and were
surrounded by astrocyte membranes.
To trace the fate of these mitochondria-rich evulsions in astrocytes, Davis et al.
targeted a red/green, acid-resistant/acid-sensitive fluorescent protein to neuronal
mitochondria. In healthy mitochondria,
red and green signals colocalize, whereas
the green fluorescence is eliminated in an
acidic lysosomal environment. The authors
confirmed that mitochondria undergoing lysosomal degradation were not in axons but
in surrounding glia (astrocytes). They also
detected degraded neuronal mitochondrial
DNA in astrocytes. The study provides compelling evidence that retinal ganglion cells
can transfer mitochondria to astrocytes for
destruction rather than sending the organelles down the axon to the cell body for recycling. In addition, Davis et al. show that a
majority of axonal mitochondria in the optic nerve head undergo degradation in surrounding astrocytes. This process therefore
represents a major route for mitochondrial
disposal from these neurons.
Retinal ganglion cells are particularly
energy-hungry cells and may demand a level
of mitochondrial turnover that exceeds axonal transport capacity. Their axons project
through a variety of target regions in the
brain, are unmyelinated in the retina but
myelinated for the remainder of their length,
and experience stressors such as light, varying intraocular pressure, and poor oxygen
supply (13). Such an environment could
stand in contrast to the more protected regions of the brain and nerve tracts, and so
this may be a specialization of these neurons.
However, one could also imagine low levels
of transcellular mitochondrial degradation
being dismissed as artifactual in these tissues or going wholly unnoticed because they
are only readily identified by electron microscopy or with a fluorescent marker. Indeed,
this phenomenon appears to be more widely
used in the nervous system, as Davis et al.
report the identification of similar mitochondria-rich protrusions in the superficial layers
of the cerebral cortex of young mice.
Davis et al. have named this process of
transcellular degradation of mitochondria
“transmitophagy.” But although cell-auton-
omous mitophagy is an autophagic event,
it remains to be determined whether axo-
nal mitochondria transferred to astrocytes
are degraded by an autophagic process or a
phagocytic event; both would result in the
association of transferred material with ly-
sosomal compartments. Key next steps in-
clude determining whether these particles
are enclosed in a double membrane-bound
vesicle, implying autophagy, or a single
membrane-bound phagosome-like vesicle.
Equally important is exploring whether
this process is regulated by autophagic,
phagocytic, or other signaling pathways.
The process of transmitophagy not only
goes against dogma—cells don’t necessarily
autonomously destroy all of their own mitochondria—but it raises many intriguing
questions about the biology of mitochondria, axons, and astrocytes. For instance,
how do mitochondria tag themselves for
disposal, cluster at the appropriate axonal
site, and load themselves into these evulsions? It is also not clear whether this transcellular degradation process is specific for
mitochondria, or is used to dispose of other
axonal organelles. How astrocytes discriminate between axonal evulsions and healthy
axonal material, and ultimately drive uptake
and disposal of the correct target is also a
curiosity. What drives the formation of evulsions, loading, and pinching off is also an
open question. The finding also raises the
question of whether signals are sent from
the axon to the astrocyte to ensure uptake.
Even if transmitophagy is rare in healthy
neuronal populations, it will be necessary
to determine whether each neuron has the
intrinsic capability to use this mechanism
to dispose of unwanted mitochondria, if we
wish to understand neuronal physiology,
and whether it is up-regulated in response
to stress or disease. Interestingly, Davis et
al. noted an increase of transmitophagy
in retinal ganglion cells after exposure to
rotenone, an inhibitor of mitochondrial
respiratory chain complex I. Autophagosomes containing mitochondria reportedly
accumulate in neurodegenerative disease
models (9, 14). In these situations, transmitophagy may compensate for interruptions in axonal transport by intracellular
aggregates or disruption of microtubule
networks. Going forward, it will be exciting
to explore a possible increase of transmitophagy as a neuroprotective target. ■
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Retinal ganglion cell axon
Astrocyte
Mitochondria
Clustering of mitochondria
Mitochondrial loading
of axonal evulsion
Astrocytic internalization
and degradation
Lysosome
Department of Neurobiology, Howard Hughes Medical
Institute, University of Massachusetts Medical School,
Worcester, MA 01605, USA. E-mail: marc.freeman@
umassmed.edu 10.1126/science.1258295
Transmitophagy. Mitochondria cluster in the axon of a
retinal ganglion cell in the optic nerve head. This forms
an evulsion that is internalized by a nearby astrocyte.
Mitochondria are then degraded in lysosomes.
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