Neonatal Hypoxia or Maternal Diabetes Delays Postnatal Development of Liver Mitochondria

Abstract

ABSTRACT. The matrix adenine nucleotide pool size of rat liver mitochondria was low at birth (2.6-3.0 nmol ATP+ADP+AMP/mg mitochondrial protein). After parturition, the pool size was increased by 50-75% within 1 h, which was sufficient for full development of state 3 respiration rates. The adenine nucleotide pool size continued to increase to 100-150% of the value at birth by 2-3 h postnatal. The ATPIADP ratio in isolated mitochondria also increased postnatally, to about double the value at birth by 3 h. There were no matrix volume changes over this postnatal period, so the increased ATP+ADP+AMP pool size and the increased ATPIADP ratio together inferred an overall increase of about 5-fold in the matrix ATP concentration under aerobic conditions. The postnatal uptake of adenine nucleotides into mitochondria occurred at a slower rate in newborns that were hypoxic (11% Oz) and in newborns of diabetic mothers (diabetes induced on day 5 of gestation by streptozotocin injection). The normal increase in matrix ATP content is responsible for the rapid stimulation of pyruvate carboxylation (an ATP-requiring matrix reaction) and this in turn contributes to the rapid postnatal onset of gluconeogenesis. The results suggest that delayed adenine nucleotide uptake into liver mitochondria may retard initiation of gluconeogenesis in newborns experiencing hypoxia, as in respiratory distress or in newborns of diabetic mothers. We speculate that this mechanism contributes to the persistent hypoglycemia that is typical of these at-risk newborns. (Pediatr Res 21: 266-269,1987) Mitochondria isolated from full-term fetal rat liver are functionally well coupled, but the rate of oxidative phosphorylation (state 3 respiration) is very low (reviewed in Reference 1). Within 1 h after birth, the state 3 rate increases to adult values (2-4). This functional maturation depends on a rapid increase in the mitochondrial adenine nucleotide content (ATP+ADP+AMP) which occurs in the immediate postnatal period (2, 4-6) In addition to activating state 3 respiration the increased adenine nucleotide pool size may also stimulate metabolic pathways that have adenine nucleotide-dependent enzymes within the mitochondrial compartment (reviewed in Reference 1). One matrix enzyme subject to this kind of control is pyruvate carboxylase. In both the newborn rat and rabbit the sudden postnatal increase in the matrix ATP concentration enhances pyruvate carboxylation rates enabling the onset of gluconeogenesis and recovery from postnatal hypoglycemia (7-9). Thus, the accumulation of adenine nucleotides into the mitochondria appears to be important for metabolic adaptation to neonatal life (see Reference 1).Received May 13, 1986; accepted October 23, 1986. Correspondence and reprint requests Dr. June R. Aprille, Mitochondria1 Physiology Unit, Department of Biology, Tufts University, Medford, MA 02155.Supported by NIH Grants HD 16936 and NS 14936.There is considerable evidence that hormones and oxygenation are important controlling factors for the subcellular red...

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“…At birth, as lungs inflate, there is a change in fetal liver circulation that results in sudden perfusion of the liver with well-oxygenated blood (12). This appears to be a permissive condition for mitochondrial uptake of AdN, since animals subjected to prolonged postnatal hypoxia fail to increase mitochondrial AdN content and related functions (12,16,54,397).…”

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“…At birth the hyperinsulinaemia continues briefly and is one of the factors involved in the natural delay in hepatic glycogenolysis ( Fig. l(b)) (Snell & Walker, 1973b and functional mitochondria1 maturation (Aprille & Nosek, 1987) which results in a transient postnatal hypoglycaemia in the first few hours of postnatal life ( Fig. l(a)).…”