Transcellular degradation of axonal mitochondria

Abstract

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.mitophagy | phagocytosis T he number, half-life, and morphology of mitochondria vary widely across cell types and are regulated by both intrinsic and extrinsic mechanisms. Mitochondria number is controlled through regulated production (1) and degradation (2), as well as by the regulated fusion and fission of existing mitochondria (3). Damaged mitochondria are removed by mitophagy, a subtype of autophagy that involves the enwrapping of mitochondria in autophagosomes that subsequently fuse with lysosomes to become autophagolysosomes (2). Implicit in the categorization of mitophagy as a subtype of autophagy is the assumption that each cell degrades its own mitochondria.Recently, we described a phenomenon at the optic nerve head (ONH) of WT mice, where evulsions originating from otherwise intact axons are engulfed and degraded by resident phagocytic astrocytes (4). Serial section-based 3D reconstructions obtained through serial block-face scanning electron microscopy (SBEM) revealed that the protrusions on axons and the evulsions near axons were common throughout the ONH in both the glial lamina, where retinal ganglion cell axons are unmyelinated, and in the adjacent myelination transition zone (MTZ). The axonal protrusions and evulsions were, on average, larger than the mean diameter of axons and contained membrane-bound organelles of unknown identity. Results Axonal Protrusions and Evulsions Within the ONH Contain Mitochondria.To determine the identity of the membranous material contained within the axonal evulsions at the ONH, a 3-mo-old WT C57BL/6J mouse was an...

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