Discovery and implications of transcellular mitophagy

Abstract

The mitochondrial quality control system regulating mitochondria biogenesis, dynamics, and degradation has been extensively studied because of its roles in normal cell homeostasis and dysfunction due to aging or disease. Mitochondria degradation is generally thought to occur by autophagy and has therefore been viewed as a cell-autonomous process. In a recent study, we demonstrated that a large fraction of retinal ganglion cell mitochondria undergo lysosomal degradation within the astrocytes of the optic nerve head. It will be important to determine whether other neurons with long axons also use transcellular mitophagy, or transmitophagy, as a primary mitochondrial quality control mechanism either under normal physiological conditions or in disease. The elucidation of the underlying molecular mechanisms is necessary to determine whether defects in transmitophagy are involved in pathogenesis and whether it should become a therapeutic target.

Keywords: astrocyte; optic nerve head; retinal ganglion cell.

Figure 1.

Degradation of axonal mitochondria may occur by several pathways. (A) Degradation of axonal mitochondria by lysosome (Ly) fusion with autophagosomes (AP) or shed mitochondria-derived vesicles locally within axons. Bidirectional arrow indicates a fission event, and mitochondrial matrix color indicates acidification state, where yellow represents neutral pH and red represents acidification, as reported by the MitoEGFPmCherry transgene. (B) Retrograde axonal transport of either autophagosome-sequestered mitochondria or dysfunctional mitochondria derived from asymmetric fission events can enable degradation of axonal mitochondria within the often-distant cell soma. (C) Axonal transmitophagy.