PROJECT SUMMARY
Gestational diabetes mellitus (GDM) is one of the major pregnancy-related complications with an incidence of
up to 18% in the United States, depending on the diagnostic criteria. More strikingly, the incidence of GDM is
expected to increase with the worldwide epidemic of obesity. GDM is associated with fetal overgrowth which
increases risk of cesarean delivery and birth trauma and thus, increases necessity for additional care. More
importantly, exposure to GDM predisposes metabolic and cardiovascular diseases in offspring, thus amplifying
the severity of this disease with additional costs for future disease prevention, intervention, and treatments.
Therefore, studies on the mechanisms of GDM are of great clinical significance. Several studies demonstrate
that placentas from GDM patients have swollen or completely destroyed mitochondria, multiple vacuoles in
trophoblast cells, coincident with the reduced ATP production and increased oxidative stress. To date, the
underlying mechanisms for these defects remain unclear. Under normal physiological conditions, damaged
mitochondria could be repaired by fission to rescue the cell from energy inefficiency and the completely damaged
mitochondria or debris will be degraded via mitophagy, a mitochondria-specific autophagy. However, to date,
our understanding of mitophagy in human placenta and its pathophysiological roles during pregnancy remains
unclear. In this application we hypothesize that placental mitophagy is impaired by the reduced AMPK signaling
in women with gestational diabetes mellitus. This hypothesis will be tested by two specific aims. In specific aim
1, we will determine whether mitophagy is impaired in GDM placenta. The main steps of autophagic pathway
such as phagophore formation, and mitophagy and mitochondrial fission will be investigated in placentas from
women with GDM and uncomplicated normal pregnancy. We expect that the main steps of autophagy, mitophagy
and mitochondrial fission are impaired in GDM placenta, which could cause the accumulation of damaged
mitochondria in GDM placenta. In specific aim 2, we will explore the role of AMPK signaling in the impaired
mitophagy in GDM placenta. Although it is known that AMPK activity stimulates mitophagy in several cell types
including cardiomyocytes, whether this regulatory mechanism is present in human trophoblast cells remains
unclear. We will first confirm that AMPK activity is reduced in GDM placentas, then explore whether the upstream
and downstream components in AMPK signaling pathway related to mitophagy are altered in GDM placentas.
To elucidate whether AMPK signaling regulates mitophagy in human placentas, the effects of AMPK activator or
inhibitor on mitophagy will be investigated in human primary trophoblast cells. Collectively, these studies will
reveal that the reduced AMPK signaling causes the impaired placental mitophagy in women with GDM, thus
yielding important insights into the study of GDM in the aspect of mitochondrial dysfunction. Understanding of
some proposed mechanisms will aid in developing potential therapeutic tools for restoring placental functions in
GDM patients.