Medicine by Alexandros G. Sfakianakis: There's an autophagy for that!

Τρίτη 10 Οκτωβρίου 2017

There's an autophagy for that!

By Christina Towers, PhD

A critical mechanism that cells use to generate nutrients and fuel metabolism is through a process called autophagy. This process is complex and involves over 20 different proteins, most of which are highly conserved across species. It involves the formation of a double membrane structure known as an autophagasome that fuses with the lysosome to facilitate the degradation of cytoplasmic material. While bulk autophagy is thought to be largely non-specific, clearing damaged proteins from the cytoplasm, recent studies have begun to highlight more selective forms of autophagy. Selective autophagy, also coined organellophagy, facilitates the degradation of specific organelles that are damaged or targeted for recycling. Thus far, researchers have begun to investigate the selective degradation of mitochondria, peroxisomes, endoplasmic reticulum (ER), nuclei, and chloroplasts in plants, all mediated through variant forms of autophagy¹.

Autophagy Process	Degraded Material
Mitophagy	Mitochondria
Pexophagy	Peroxisomes
Reticulophagy	ER
Nucleophagy	Nuclei
Chlorophagy	Chlorplasts

The most well studied of these processes is undoubtedly mitophagy, involving the turnover of mitochondria. Mitochondria are the power houses of the cell generating ATP that fuels metabolism. They also play crucial signaling roles during cell death, and clearance of damaged mitochondria is critical to maintain cellular and tissue homeostasis. Mitophagy can be induced by several stimuli and cellular stressors including hypoxia, chemical uncouplers, ROS, and of course damaged mitochondria.

autophagy

While all organelle selective forms of autophagy utilize the basic autophagy machinery, each has a set of specific machinery proteins and receptors. In the case of mitophagy that would include the proteins, PINK1 and PARKIN². The serine/threonine phosphatase, PINK1, is usually imported into the inner mitochondrial membrane, however, when the mitochondrial membrane potential is compromised, PINK1 accumulates on the outside of the membrane where it signals the recruitment of the E3 ubiquitin ligase PARKIN to the mitochondrial membrane. Together these proteins generate a mitophagy signal by ubiquitinating proteins that are recognized by autophagy receptors. There are PARKIN independent forms of mitophagy, and likewise, PARKIN can have mitophagy independent roles in the mitochondria as well¹. Although slightly different across species, in mammals, the critical mitophagy receptors include p62, BNIP3L, BNIP3, FUNDC1, NDP52, TAX1BP1 and OPTN³.

The relevance of mitophagy to human disease is apparent by the strong link between both the PINK1 and PARKIN genes in familiar Parkinson's disease, a progressive disorder stemming from the death of dopaminergic neurons in the brain⁴. While there has been a recent focus in the field on different forms of selective autophagy, beyond mitochondrial degradation, there is still much to be learned about the specific proteins, receptors, and autophagic machinery important for each of the organelle specific processes and most importantly their role in disease.

Learn more about selective autophagy

Anding, A. L. & Baehrecke, E. H. Cleaning House: Selective Autophagy of Organelles. Dev Cell 41, 10-22, doi:10.1016/j.devcel.2017.02.016 (2017).
Matsuda, N. et al. PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy. J Cell Biol 189, 211-221, doi:10.1083/jcb.200910140 (2010).
Lazarou, M. et al. The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nature 524, 309-314, doi:10.1038/nature14893 (2015).
Valente, E. M. et al. Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science 304, 1158-1160, doi:10.1126/science.1096284 (2004).