[Catalyst 2018]

Mitochondrial Health
IMPLICATIONS FOR BREAKTHROUGH CANCER TREATMENT
SARAH KIM
B
eginning in the late 1980s, health
disorders and genetic diseases have
become increasingly attributed to the
mitochondria. Current research projects
use model organisms to understand the
implications of mitochondrial health on the
whole organism. Some of the most fruitful
research has been performed using the
model organism Caenorhabditis elegans, or
C. elegans. C. elegans is a type of nematode
(roundworm) that is only 1 millimeter in
length. Most viewers peer into a microscope
of these nematodes and see modest, squirmy
lines. Dr. Natasha Kirienko peers into the
microscope and sees limitless potential for
discovery. In an attempt to redefine disease
treatment at a global level, Dr. Kirienko
studies mitochondria surveillance pathways
and their implications on genetics and cancer
medicine.
Dr. Kirienko was brought to Rice University
by a $2 million grant from the Cancer
Prevention Research Institute of Texas
(CPRIT). As an undergraduate and graduate
student in Russia, Dr. Kirienko didn’t have
the opportunities or equipment to pursue
the research she was interested in. Coming
to America, however, she found herself with
access to advanced lab equipment and a
relatively enormous stipend—compared
to her maximum stipend of $12/month in
Russia—with which she could do whatever
she wanted. “Suddenly, the sky is your limit,”
she declared, as a sure smile reached her
eyes. “I didn’t need any encouragement to
work hard.” Dr. Kirienko’s mindset has been
infectious, as it has definitely motivated
Elissa Tjahjono, a graduate student currently
working in the Kirienko Lab. Dr. Kirienko
elaborates on how “hardworking and
motivated” Ms. Tjahjono was during her
studies and how her determination has led
her into graduate school, allowing her “to do
substantial amount of work in a year or so.”
Ms. Tjahjono was the first author of a recent,
monumental paper in Dr. Kirienko’s lab on a
mitochondrial surveillance pathway important
in the pathogenesis of Pseudomonas
aeruginosa, a bacteria that affects cell iron
availability and causes organism death. 1
Dr. Kirienko’s fascination with the
mitochondria began in graduate school.
She had read about a particular gene motif,
or a distinct sequence of DNA, called the
Ethanol Stress Response Element (ESRE).
This motif had been identified by different
scientists seven different times, and it was
shown to be upregulated (expressed more
as a gene) by ethanol-induced heat shock
(heat shock occurs when a cell is subjected
to a higher temperature than ideal). 1 During
Mitochondrial
diseases have
now become
the number
one genetic
disorder
her PhD studies, Dr. Kirienko discovered an
anomaly: a genetic mutant that was actually
supposed to reduce expression of the ESRE
gene instead caused upregulation. Further,
she found that the mutant was sensitive
to not just one , but multiple stressors. So,
“there was this puzzle [relating to ESRE]
that [involved] multiple conditions that
were different from each other.” She began
asking the questions: what is the underlying
mechanism? What triggers ESRE activation?
This led into her postdoctoral studies, during
which she researched interactions between
C. elegans and its accompanying pathogen,
Pseudomonas aeruginosa. During that time,
Dr. Kirienko and her colleagues found a
siderophore (iron carrier) called pyoverdine,
produced by P. aeruginosa, kills C. elegans by
causing severe mitochondrial damage. Almost
all living organisms require iron for their
survival, but it is difficult to acquire iron from
the environment. Animals have complicated
immune systems that limit the ability of
pathogens to acquire iron during infection. 2
Pyoverdine has evolved to surmount this
difficulty, and it is capable of getting inside
of host cells, taking away iron, and bringing
it back to bacteria. Pyoverdine, she found,
can remove up to a third of iron (III), which
is about 20-25% of iron within the host. This
results in organismal death. 1
How are the two distinct concepts of ESRE
and pyoverdine related, one may ask? At Rice,
Dr. Kirienko found that the ESRE pathway
was also upregulated after exposure to
pyoverdine, leading her to understand that
pyoverdine exposure and heat shock are
two very different stressors. It also led her
to draw the connection between ESRE and
mitochondrial damage. ESRE is upregulated
in mutants that are affected by a variety of
stressors. Pyoverdine is a direct stressor
that upregulates ESRE in the mitochondria.
According to the two previous statements,
there must be some kind of association
between ESRE and mitochondrial damage.
With this juncture acting both as a conclusion
and a foundation, the Kirienko lab took the
next step. They used small molecule drugs
such as rotenone and antimycin (known
mitochondrial poisons) to test the possibility
of the effects of ESRE on mitochondrial
damage. After much experimentation in the
lab, they “were able to link this presence of
[ESRE] in the promoter of effector genes of
mitochondrial damage.”
Now, the Kirienko lab is working on
understanding how pyoverdine is produced
in bacteria. Testing for drugs that may inhibit
this pyoverdine factor, the lab recently
found small molecules that can prevent
pyoverdine synthesis or function. The tests
are on a path to success, and a collaborator is
24 | CATALYST