In our Special Topics analysis on autophagy research
over the past decade, the work of Dr. Eiki Kominami ranks
at #5 by total number of papers, #6 by total number of
citations, and #11 by citations per paper, based on 51
papers cited a total of 3,245 times.
Essential Science IndicatorsSMfrom
Reuters, Dr. Kominami's record includes 115 papers, the
majority of which are classified under either Biology &
Biochemistry or Molecular Biology & Genetics, cited a
total of 5,112 times between January 1, 1999 and August 31,
2009. Dr. Kominami is an Emeritus Professor and President
of Juntendo University in Tokyo, Japan.
In the interview below, he
about his highly cited research.
Would you tell us a bit about your
educational background and research experiences?
My M.D. was conferred from Okayama University in 1968. After clinical
training as a resident in gastroenterology at Okayama University Hospital
for several years, I decided to enter the path to live as a scientist and
got a Ph.D. in medicine at Tokushima University in 1975. I worked for two
years (1978-1979) as an assistant professor at the Biochemical Institute of
Freiburg University, West Germany.
After returning to Japan in 1980, I worked as an associate professor at
Tokushima University Institute for Enzyme Research. In 1988, I landed a
professorship in the Department of Biochemistry at Juntendo University,
School of Medicine, and served out a term until reaching retirement in
March, 2009. I have currently been the President of Juntendo University
What first interested you in autophagy, and is
there a specific aspect of autophagy research on which you
When I was at Tokushima University from 1980 to 1988, my interest in
biochemical studies was the regulation of lysosomal proteolysis. In 1984
there was a report in the Annual Meeting of the Japanese Biochemical
Society about an isolation method for autolysosomes from livers of
leupeptin-treated rats. Using this technique, I found that many proteins
from cytosol and various organelles are incorporated into autolysosomes
non-selectively in starved rats.
I am now interested in how autophagy or autophagy machinery is involved in
metabolic regulation of various organs via lysosomal hydrolysis, including
proteolysis, and how dysregulation of autophagy occurs in various
One of your most-cited papers in our analysis is
the 2006 Nature article, "Loss of autophagy in the central
nervous system causes neurodegeneration in mice," (Komatsu M, et
al., 441:880-4, 15 June 2006). Would you talk a little bit
about this paper, its findings, and why it is so highly
In 2005, a year before the publication of this Nature article, our
group published the first paper concerning autophagy-deficiency in mouse
liver (Komatsu M, et al., "Impairment of starvation-induced and
constitutive autophagy in ATG7-deficient mice," J. Cell Biol.
169: 425-34, 9 May 2005). Phenotype analyses revealed some
characteristics of autophagy-deficient liver, many of which were well
understood as a direct effect of autophagy impairment: marked accumulation
of cell proteins occurred as a result of loss of autophagic proteolysis,
which eventually resulted in hepatomegaly accompanying significant
inflammatory responses. Unexpectedly, numerous ubiquitin-positive
aggregates were found to accumulate in autophagy-deficient hepatocytes. As
autophagy deficiency did not affect the proteolytic activities of
ubiquitin-proteasome system, this unique phenotype attracted our attention.
We then decided to create brain-specific autophagy-deficient mice to
compare the phenotype of autophagy-deficient brain with that of
autophagy-deficient liver. Surprisingly, these brain-specific
autophagy-deficient mice exhibited behavioral defects including abnormal
limb-clasping reflexes and disability in coordinate movements. These
symptoms are typically observed in various neurodegenerative diseases such
as Alzheimer's disease, Huntington's disease and Parkinson's disease. Our
report clearly demonstrated for the first time that autophagy significantly
contributes to maintaining cell health by degrading aged or damaged
In this respect, our findings have drawn considerable attention, which is
the most likely reason for many citations of this paper. Of course, we
could confirm that many ubiquitin-positive aggregates were also present in
autophagy-deficient brain, supporting that the accumulation of
ubiquitylated proteins is a common phenotype of autophagy deficiency.
Last year, your group published a paper in
Autophagy, "Loss of Pten, a tumor suppressor, causes the
strong inhibition of autophagy without affecting LC3 lipidation,"
(Ueno T, et al., 4: 692-700, 1 July 2008). Could you tell our
readers something about this paper?
Using a cultured cell system, it has been previously reported that active
class III-phosphatidylinositol3-kinase complex is essential for autophagy,
whereas activation of class I phosphatidylinositol 3-kinase causes
autophagy suppression. Pten (phosphatase and tensin homolog deleted on
chromosome ten), a tumor suppressor, functions as a negative regulator of
the class I phosphatidyl-inositol 3-kinase/Akt pathway, thus antagonizing
insulin-dependent cell signaling. Hepatocyte-specific Pten-deficient mice
created by one of our collaborators' groups were a useful experimental
system for investigating the effects of hyper activation of the class I
PI3-kinase/Akt pathway on cell metabolism.
"As autophagy deficiency did not affect the
proteolytic activities of ubiquitin-proteasome
system, this unique phenotype attracted our
The targeted deletion of Pten in mouse liver leads to insulin
hypersensitivity and the upregulation of the phosphatidyl-inositol
3-kinase/Akt signaling pathway with elevated levels of phosphorylated Akt
and the development of adenomas and hepatocellular carcinomas. We
extensively investigated these conditional knockout mice and found that
hepatic autophagy was markedly suppressed. The autophagy suppression was
mainly attributable to the inhibition of autophagosome formation, although
the loss of Pten did not affect the autophagy-specific protein conjugation
reaction to form Atg12-Atg5 and LC3-II.
How has our knowledge of autophagy changed over the
I should say that our knowledge of autophagy has been tremendously
increased or enlarged during the past 10 years. The article published in
Nature by Mizushima et al. in 1998 ("A protein
conjugation system essential for autophagy," 395: 395-8, 24 September
1998) surprised many cell biologists who had been engaged in the study of
autophagy as well as other cellular protein degradative systems in that a
unique protein conjugation system similar to that of ubiquitin proteasome
plays an indispensable role in autophagy. The paper certainly became an
epoch-making landmark in the history of autophagy, not because it solved
difficult questions of autophagy in a single burst (the ATG conjugation
system still remains the Gordian knot of autophagy), but because it clearly
demonstrated which of the ATG genes play in the center.
This work hinted at gene-knockout approaches that have become a royal road
to understanding physiology and pathology of autophagy. One can easily
recognize that diverse functions of autophagy, including roles in
cytoplasmic quality control, metabolic compensation, innate immunity,
cell-defense against microbial infection, etc., have been elucidated during
the subsequent 10 years. Many findings have been accomplished using
ATG-gene knockout mice, flies, and C. elegans.
Why is it important to study autophagy?
Autophagic functions are broadly associated with various pathologies such
as cancer, neurodegeneration, cardiac disease, diabetes, and infections.
New insights into the molecular mechanisms of autophagy could lead to a
discovery of potential drug targets. However, autophagy is a fundamental
homeostatic process and an essential cell-protective mechanism. An
important issue of medicine in the 21st century is how to prevent diseases,
rather than fight against them. I believe that the more insights we can
obtain into the mechanism of autophagy, the more procedures we can get to
keep us healthy and prolong a life span. For example, it's known that
autophagic activities at the individual level decline along with aging.
Creating medicine to stimulate autophagy will bring us more peaceful and
pleasant days at our older age.
Eiki Kominami, M.D. & Ph.D.
Kabeya Y, et al., "LC3, a mammalian homologue of
yeast APG8P, is localized in autophagosome membranes after
processing," EMBO J. 19(21): 5720-8, 1 November
2000. Source: Essential Science Indicators from