Interview Date: August 2009
From the Special Topic of
According to our Special Topics analysis of autophagy
research over the past decade, the scientist whose work
ranks at #1 by total citations is Dr. Noboru Mizushima,
based on 82 papers cited a total of 7,376 times. Eleven of
these papers are also ranked among the most-cited over the
past decade and over the past two years.
Essential Science IndicatorsSM from
Reuters, Dr. Mizushima's work, which is largely
classified in the fields of Molecular Biology &
Genetics and Biology & Biochemistry, includes 92 papers
cited a total of 7,628 times between January 1, 1999 and
April 30, 2009.
At present, Dr. Mizushima is a Professor in the Department of
Physiology and Cell Biology at Tokyo Medical and Dental University. In
2007, he won the FEBS Letters Young Scientist Award.
In the interview below,
ScienceWatch.com talks with Dr. Mizushima about his
work in autophagy.
Would you tell us a bit about your
educational background and research experiences?
I graduated from the School of Medicine at Tokyo Medical and Dental
University in 1991, and finished the internal medicine residency program in
1993. I started my research career with studies on molecular immunology and
received a Ph.D. in 1996. After that, I joined Dr. Yoshinori Ohsumi’s
laboratory at the National Institute for Basic Biology as a postdoctoral
fellow, where I worked for seven years on the molecular mechanism and
physiological role of autophagy in yeast and mammals. In 2004, I
established my own laboratory at the Tokyo Metropolitan Institute of
Medical Science and then, in 2006, I joined Tokyo Medical and Dental
University as a professor of physiology and cell biology.
What first interested you in autophagy?
Soon after I received my Ph.D., I happened to read a short Japanese review
article by Dr. Ohsumi. At that time, Dr. Ohsumi had already isolated
autophagy-defective (apg) yeast mutants and identified some
autophagy-related genes based on the apg mutants. What fascinated me in the
article was that all of them were new genes whose functions were not easily
determined by their amino acid sequences. Although autophagy is conserved
in all eukaryotes, molecular biological studies were very limited.
Autophagosomes in starved fibroblasts.
Photo by Drs.
Chieko Kishi and Noboru Mizushima
Inspiration hit me that the studies on yeast autophagy might lead to
mammalian autophagy. Thus, I joined Dr. Ohsumi’s laboratory and
studied the molecular mechanism of yeast autophagy. It was very lucky for
me to discover a unique ubiquitin-like conjugation system required for
autophagy, which is now called the Atg12 conjugation system.
One of your highly cited papers in our analysis is
the 2001 Journal of Cell Biology paper, "Dissection of
autophagosome formation using Apg5-deficient mouse embryonic stem
cells." Would you tell us about this paper, and why you think it's so
Although autophagy was first discovered in mammalian cells in 1960s,
molecular studies on mammalian autophagy have been very limited. During our
analysis of yeast autophagy, we soon realized that most of the yeast
autophagy genes are well conserved in higher eukaryotes. I therefore
generated mouse embryonic stem cells in which a critical autophagy gene was
deleted (Atg5-/- cells). In this 2001 JCB paper, we reported
function of Atg5 in autophagosome formation and demonstrated live images of
autophagosome formation for the first time using GFP-tagged Atg5.
Furthermore, since this was the first mammalian cell line whose autophagic
activity was completely suppressed, many researchers have used this cell
line to analyze the role of autophagy in cultured cells. Using the
embryonic stem cells, we later generated Atg5-/- mice, with which we have
discovered several important roles of autophagy in mice (Kuma et
al. 2004, Hara et al. 2006, and Tsukamoto et al.
Another of your highly cited papers is the 2004
Molecular Biology of the Cell paper, "In vivo
analysis of autophagy in response to nutrient starvation using
transgenic mice expressing a fluorescent autophagosome marker." Please
tell us about this paper - its aims, methods, and findings.
At that time, the role of autophagy in mammals was still poorly understood.
Moreover, we did not exactly know where and when autophagy is induced
in vivo, largely because methods for monitoring autophagy were
limited and unsatisfactory. The most standard method was conventional
electron microscopy. However, this method requires considerable skill and a
lot of time, and sometimes it is difficult to distinguish autophagic
vacuoles from other structures just by morphology.
To monitor autophagy simply and accurately, we generated a transgenic mouse
systemically expressing GFP-LC3 that labels autophagosomes. Using this
transgenic mouse, we can now detect autophagosomes in every tissue easily
by fluorescent microscopy. We have observed that autophagy is induced in
almost all tissues except the brain following starvation. We also used this
mouse model in later papers, in which we found that autophagy is activated
after birth (Kuma et al. 2004) and fertilization (Tsukamoto et al.
2008). And now more than 300 laboratories use this autophagy-indicator
Earlier this year, you published a paper in the
January 2009 issue of Autophagy, "Role of ULK-FIP200 complex
in mammalian autophagy FIP200, a counterpart of yeast Atg 17?" Could
you tell our readers something about this paper?
Autophagy-related genes are well conserved from yeast to mammals. However,
recent studies have identified several mammalian-specific autophagy genes.
One of them is FIP200, which is discussed in this short review. FIP200,
also known as RB1CC1, has several previously known functions such as in
cell adhesion, cell-cycle regulation, and RB gene expression. We also
discovered that FIP200 is essential for autophagy. One interesting thing is
that FIP200 has no apparent homology to any known yeast Atg proteins,
although its function may be similar to yeast Atg17. We also found Atg101,
which is absent in yeast. These studies imply that although autophagy
machinery seems to be conserved from yeast, mammals may have their own
How has our knowledge of autophagy changed over the
"...although autophagy machinery
seems to be conserved from yeast, mammals may
have their own additional
The autophagy research field has dramatically changed during the past
decade. A lot of autophagy-specific molecules have been identified in
various species, including humans. In addition to the well-known role of
autophagy as a starvation adaptation response, many unexpected roles of
autophagy have been discovered. For example, autophagy turned out to be
important for neonatal survival, preimplantation development, prevention of
neurodegeneration, killing of intracellular microorganisms, antigen
presentation, tumor suppression, anti-aging, etc.
Where would you like to take your research on
autophagy in the next decade?
One remaining important issue is that how autophagy is regulated within
cells and in whole animals. We have recently published that mTOR directly
regulates the autophagy factors, but upstream signaling is not very clear.
Furthermore, although it has been suggested that insulin is a major
regulatory factor of autophagy in vivo, contribution of other
hormones mostly remains unclear.
Another topic would be organelle turnover. Since organelles are too big to
be degraded by proteasomes, autophagy should be very important. Recent
studies have shown that autophagy can selectively degrade some proteins and
organelles. Studies of organelle turnover will be also important for
understanding of pathogenesis of human diseases, such as Parkinson’s
disease, in which mitochondrial quality control is reported to be critical.
What would you say the "take-home message" about
your work should be?
Protein turnover may be one of the old topics in life science research, but
there are still a lot of interesting things that have remained
undiscovered. Another thing that I would like to emphasize is that all
these important findings were brought to us following the breakthrough
experiments using yeast cells. Yeast genetics is still a powerful tool in
Noboru Mizushima, M.D., Ph.D.
Department of Physiology and Cell Biology
Tokyo Medical and Dental University
KEYWORDS: AUTOPHAGY, YEAST, APG, MAMMALS, ATG12 CONJUGATION
SYSTEM, ATG5, TRANSGENIC MICE, IN VIVO, AUTOPHAGY