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.
Gestational diabetes mellitus (GDM) presents a heavy socioeconomic burden because it not only increases the risk of maternal and fetal adverse outcome, but also predisposes long term health problems in offspring. We propose to investigate whether reduced AMPK signaling impairs mitophagy in placentas of women with GDM. The expected findings will yield important insights into the study of placental mitochondrial dysfunction, and into potential therapeutic means for GDM and other metabolic disorders during pregnancy.
