International Journal of Human Nutrition and Functional Medicinewww.IntJHumNutrFunctMed.Org
2015 Final PDF
What have been your main areas of research? How did
you become interested in studying mitochondria and
the effects of toxic chemicals on bioenergetics?
I developed radioimmunoassays during my PhD course,
studying hormone (including insulin) measurement. After
being appointed as a faculty staff member in Department
of Internal Medicine, I had an opportunity to do research
in United States in my choice of field for 2 years.
I elected first to study endocrine hypertension at
Boston University (with J Melby) by the suggestion of
Professor Min. Dr Melby had an idea that low-renin
hypertension (a special form of hypertension) is due to
some unknown chemical compound in blood, produced by
our body. Recently a substance known as endocrine
disrupting chemical (EDC), Bisphenol A, has been
reported to increase blood pressure. I studied with rat
adrenal cytosol to pick up that signal, but could not find
In 1980 I moved to Joslin Diabetes Research
Center to get exposure to the diabetes field. I studied with
Professor Thomas T Aoki on the energy substrate
metabolism in subjects with diabetes and during exercise.
I started to realize the importance of mitochondrion at that
time, and I found that glucose was not burned completely
as it underwent mitochondrial metabolism (TCA cycle
and electron transport chain). Insulin's stimulation of all
the process suggested a new concept at that time—insulin
resistance. After coming back to Seoul, I found I could not
use any of those high-tech methods, due to lack of money,
machines, and other contingencies.
Then I was exposed to the epidemiology of
diabetes by participating in the International Diabetes
Federation/WHO epidemiology training course held in
Cambridge in 1983. Leaders in diabetes epidemiology,
including Peter Bennet, US NIDDK, told me about the
current state of diabetes research. I was surprised to find a
lack of understanding among diabetes experts on the
cause(s) of diabetes. I started to think
my own way
late 1980s. The following were key considerations, which
I published in
Journal of the Korean Diabetes Association
in early 1994.
1) It was self-evident that environmental factor(s) are the
most important causative agent of the diabetes
epidemic. The word ‘epidemic’ suggested it.
2) It was also apparent that the agent is ‘not-infectious’.
3) The factor or factors causing diabetes were being
introduced by societal modernization/westernization. I
thought at first fungal toxin(s) might be the major
player, which proved very unlikely. I could not figure
them out easily.
Then one friend educated me that free radical damage in
mitochondrial DNA (mtDNA) occurs almost 10-times
faster than in nuclear DNA. In late 1980s, mutation in
mtDNA (now known as MELAS mutation at the 3243
position) had just been reported to cause diabetes.
4) I started to look at mitochondria as a target for the
unknown environmental factor causing diabetes. Very
few people were studying mitochondria at that time. It
occurred to me if mitochondrial damage is caused by
the chemicals, it could explain insulin deficiency,
insulin resistance, and genetic susceptibilities.
To understand the state of mtDNA, I simply took
leukocytes of diabetic subjects and let my students do
southern blot of mtDNA. We found that mtDNA density
was lower in diabetics than in healthy controls. This was
in 1994. Then by early 1995, Dr Ronald Khan, Director of
Joslin Research Center, reported that mitochondrial DNA
abnormality in diabetes is indeed low, but concluded it is
to the diabetic state. However, our group
appreciated the possibility that mitochondrial dysfunction
or mtDNA abnormality could be the
of diabetes, as
demonstrated by mtDNA mutation. Dr Khan's report was
huge blow to me, but also it provided an opportunity—
very little competition. Gerry Shulman and his colleagues
at Yale University were one of few groups who
continuously reported the presence of mitochondrial
dysfunction in insulin resistance. However, the question
of whether it is primary or secondary remains with us day.
By 2000, my group made some advances. Most
importantly, we found that mtDNA depletion in peripheral
blood precedes the onset of diabetes in a community-
based cohort by using the so-called nested case-control
design. Furthermore, reduced mtDNA level were found to
correlate with blood pressure, abdominal obesity, and
other parameters of metabolic syndrome.
We also established that mtDNA is an
independent genetic susceptibility factor of diabetes. We
made mtDNA-depleted cells and showed they are insulin-
resistant. We were among few groups who appreciated
this. It was time to think about "
what causes the
" I looked at an obesity map
published by the US CDC, and I saw that the obesity
epidemic occurred mostly around the Mississippi river
valley and eastern states. I realized that pesticide use
might be a cause. Atrazine was the most widely used
chemical, herbicide. It was known to cause mitochondrial
damage. We started to feed atrazine to rats to see if it
"We made mtDNA-depleted cells and showed they are
insulin resistant. Few people recognized those works. It was
time to think "what caused the mitochondrial dysfunction?" I
looked obesity map published by US CDC. Obesity epidemic
occurred mostly around the Mississippi river valley and
eastern states. I realized pesticides use might be a cause.
Atrazine was the most widely used chemical, herbicide. It
was known to cause mitochondrial damage."