Fatal preemie disease due to mitochondrial failure
A life-threatening condition preventing gut development in premature infants may be triggered by a disruption in the way the body metabolizes energy from Mitochondria.
In research published in the journal Development, scientists found a link between necrotizing enterocolitis (NEC) — a major cause of death in babies born before 36 weeks gestation — and the disruption of a process known as mitochondrial metabolism. Mitochondrial metabolism is how a cell's mitochondrial "batteries" create respiration, thus the production of energy in our cells. Mitochondria use one oxygen atom to form two adenosine triphosphate (ATP) molecules.
"At this time, we think the discovery that mitochondrial metabolism is a hallmark of mature intestinal development may provide a new way to screen and identify NEC before children are born — or at the time of their birth. Early detection of NEC would give doctors a chance to head off the disease before it's too late."
Michael Verzi PhD, Assistant Professor, Department of Genetics, Rutgers University-New Brunswick's School of Arts and Sciences, and lead author of the study.
There is no known cause for NEC which occurs in up to 10 percent of premature infants and is fatal to 25 - 35 percent. Babies with NEC — which presents as a swollen belly, fever and constipation usually within two weeks of birth — are treated with intravenous fluids, antibiotics and surgery. Research indicates NEC is much less common in babies fed breast milk. But, even successfully treated NEC infants can have problems absorbing nutrients as they continue to grow.
The Rutgers study indicates a gene deficiency might be what stops mitochondrial metabolism from occuring at the end of gestation, a time when the intestines are becomming fully formed.
Although more research is needed to determine its exact cause, scientists believe one possibility for the deficiency may be a mother's exposure to environmental toxins during pregnancy which inhibit her process of cellular phosphorylation [the addition of a phosphate group to a molecule to either turn a protein enzyme on or off].
"Without this metabolic process, the intestine cannot fully mature," Verzi explains. "If children are born before their intestine is fully developed, it can lead to severe inflammation that leads to tissue death."
Verzi and his team examined data from premature infants who died as a result of NEC. They then conducted studies on mice in which the gene needed to regulate mitochondrial function was inactivated in the developing intestine. When the mitochondrial metabolism was blocked, the intestine was not able to mature.
"This shift in metabolism during intestinal development has never been recognized as crucial for intestinal growth to take place. We think that the deficiencies in this important mitochondrial function serve not only as a cause for NEC but also could become a marker to help identify babies at risk."
Michael Verzi PhD
During late gestation, villi extend into the intestinal lumen to dramatically increase the surface area of the intestinal epithelium, preparing the gut for the neonatal diet. Incomplete development of the intestine is the most common gastrointestinal complication in neonates, but the causes are unclear. We provide evidence in mice that Yin Yang 1 (Yy1) is crucial for intestinal villus development. YY1 loss in the developing endoderm had no apparent consequences until late gestation, after which the intestine differentiated poorly and exhibited severely stunted villi. Transcriptome analysis revealed that YY1 is required for mitochondrial gene expression, and ultrastructural analysis confirmed compromised mitochondrial integrity in the mutant intestine. We found increased oxidative phosphorylation gene expression at the onset of villus elongation, suggesting that aerobic respiration might function as a regulator of villus growth. Mitochondrial inhibitors blocked villus growth in a fashion similar to Yy1 loss, thus further linking oxidative phosphorylation with late-gestation intestinal development. Interestingly, we find that necrotizing enterocolitis patients also exhibit decreased expression of oxidative phosphorylation genes. Our study highlights the still unappreciated role of metabolic regulation during organogenesis, and suggests that it might contribute to neonatal gastrointestinal disorders.
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