Placental metabolic reprogramming: do changes in the mix of energy-generating substrates modulate fetal growth?

Abstract

Insufficient oxygen leads to the cessation of growth in favor of cellular survival. Our unique model of high-altitude human pregnancy indicates that hypoxia-induced reductions in fetal growth occur at higher levels of oxygen than previously described. Fetal PO(2) is surprisingly high and fetal oxygen consumption unaffected by high altitude, whereas fetal glucose delivery and consumption decrease. Placental delivery of energy-generating substrates to the fetus is thus altered by mild hypoxia, resulting in maintained fetal oxygenation but a relative fetal hypoglycemia. Our data point to this altered mix of substrates as a potential initiating factor in reduced fetal growth, since oxygen delivery is adequate. These data support the existence, in the placenta, of metabolic reprogramming mechanisms, previously documented in tumor cells, whereby HIF-1 stimulates reductions in mitochondrial oxygen consumption at the cost of increased glucose consumption. Decreased oxygen consumption is not due to substrate (oxygen) limitation but rather results from active inhibition of mitochondrial oxygen utilization. We suggest that under hypoxic conditions, metabolic reprogramming in the placenta decreases mitochondrial oxygen consumption and increases anerobic glucose consumption, altering the mix of energy-generating substrates available for transfer to the fetus. Increased oxygen is available to support the fetus, but at the cost of less glucose availability, leading to a hypoglycemia-mediated decrease in fetal growth. Our data suggest that metabolic reprogramming may be an initiating step in the progression to more severe forms of fetal growth restriction and points to the placenta as the pivotal source of fetal programming in response to an adverse intrauterine environment.

Fig. 1. Oxygen delivery and consumption at low and high altitude

Summary of the data calculated from blood flow and blood gas measurements describing maternal and fetal oxygenation, maternal oxygen delivery and fetal oxygen consumption at 400 m (low) and 3600 m (high) altitude.

Fig. 2. Glucose delivery and consumption at low and high altitude

(A) Maternal arterial and venous glucose concentrations at 400 m (low; red) and 3600 m (high; blue) altitude. (B) Uteroplacental delivery of glucose at 400 m and 3600 m, normalized per kg of uterine contents. (C) Umbilical venous and arterial blood glucose concentrations at 400 m and 3600 m. (D) Fetal uptake of glucose at 400 m and 3600 m, normalized per kg fetus.

Fig. 3. Responses to hypoxia

Cellular responses to hypoxia, including the recently described “metabolic reprogramming”.

Fig. 4. Hypoxia inducible factor1 (HIF-1)-mediated inhibition of mitochondrial electron transport

Mechanisms which reduce mitochondrial oxygen consumption. (A) Nitric oxide (NO) inhibition of mitochondrial electron transport chain complex IV, cytochrome c oxidase, stimulated by HIF-1. (B) Inhibition of mitochondrial electron transport chain complex II (succinate dehydrogenase, SDH) mediated by HIF-1 suppression of SDH subunit B expression.

Fig. 5. Diversion of glucose carbon flux away from oxidative metabolism

(A) HIF-1 stimulation of the inhibition of pyruvate dehydrogenase (PDH) through pyruvate dehydrogenase kinase (PDK)-mediated phosphorylation. (B) HIF-1 stimulation of the expression of the lactate dehydrogenase A subunit.

Fig. 6. Pathways of hypoxia inducible factor1 (HIF-1)-mediated alterations in mitochondrial biogenesis and autophagy

The partial signaling pathways by which hypoxia, via HIF-1, alters the rates of (A) mitochondrial biogenesis and (B) mitochondrial autophagy (from Zhang et al., 2008; Zhang et al., 2007).

Fig. 7. Model of growth restriction processes stimulated by hypoxia