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As a scientist, we can uncover novel biological mechanisms by using our hands and by using our ideas and creativity. Every day is full of scientific activities with many discussions and many experiments. These kind of things drove me to become a scientist. When I was a high school student, I was very interested in chemistry; I didn’t care about biology. But during my Ph.D. studies, I realized that biology is much more important for our health. That’s why I decided to become a molecular biologist.

Mitochondria have a membrane potential that it uses to produce ATP. This membrane potential is also important for protein import. Without a membrane potential, mitochondrial matrix proteins cannot go into the mitochondria. This is a fundamental principle of mitochondrial protein import. But in 2008, an interesting paper came out from Richard Youle’s group at the NIH in the United States. They found that a cytosolic protein called Parkin is selectively recruited to damaged mitochondria that don’t have a membrane potential and triggers elimination of these damaged mitochondria by autophagy. I’m very interested in this process. How do mitochondria without a membrane potential recruit Parkin? I wanted to know the molecular mechanism of Parkin translocation so I started studying mitochondrial elimination.

To keep cellular homeostasis, synthesis of new mitochondria is of course important, but the degradation of bad mitochondria is also important. In 2008, Richard Youle’s group found that Parkin is essential for mitochondrial elimination. Two years later, in 2010, several groups including ours, independently identified that PINK1 is also essential for elimination and functions upstream of Parkin translocation. Surprisingly, Parkin and PINK1 have both been identified as products of genes mutated in Parkinson’s disease. Parkinson’s disease is one of the most frequent neurodegenerative diseases. Several papers suggest that accumulation of damaged mitochondria in neuronal cells causes the Parkinson’s disease phenotype.

Parkin is an E3 ubiquitin ligase, which means that Parkin is an enzyme that puts ubiquitin onto substrates. In this case it puts ubiquitin onto proteins on damaged mitochondria. Ubiquitin was primarily known to be important for degradation of individual proteins by targeting them to the proteasome, but recently, we and others found that in some cases, ubiquitination is essential for the autophagy degradation pathway. Proteasomes degrade proteins one by one, but autophagy degrades bigger targets such as protein complexes, aggregates, and even organelles. We call autophagy of mitochondria, mitophagy.

We've investigated how Parkin and PINK1 work together to put ubiquitin on damaged mitochondria, but we still didn’t know how ubiquitin-coated mitochondria are recognized by the autophagy machinery. Autophagy adaptors may be a key to linking ubiquitin to the autophagy machinery. Mammalian cells have five different autophagy adaptors, and all five adaptors contain ubiquitin binding domains and are recruited to the mitochondria. Furthermore all five adaptors contain ATG8 interacting motifs. ATG8 is a part of the autophagic machinery that is covalently attached to autophagic membranes. So many groups thought that autophagy adaptors could act as a bridging molecule, recruiting ATG8 and autophagic membranes to ubiquinated mitochondria. However, only two adaptors, called NDP52 and optineurin, are essential for mitochondrial elimination. We found that optineurin binds to not only ATG8, but also to another autophagy core protein, ATG9, and another group found that NDP52 binds FIP200. ATG9 and FIP200 are also essential autophagy proteins and they are important for the de novo synthesis of autophagic membranes. So now we think that optineurin and NDP52 are recruited to ubiquitinated mitochondria and begin synthesis of autophagic membranes to encapsulate the mitochondria. ATG8 is also important for encapsulation, but we found that ATG9-dependent initiation of de novo membrane synthesis is an important earlier step in this process.