Mitochondrial dysfunction in alveolar and white matter developmental failure in premature infants

Abstract

At birth, some organs in premature infants are not developed enough to meet challenges of the extra-uterine life. Although growth and maturation continues after premature birth, postnatal organ development may become sluggish or even arrested, leading to organ dysfunction. There is no clear mechanistic concept of this postnatal organ developmental failure in premature neonates. This review introduces a concept-forming hypothesis: Mitochondrial bioenergetic dysfunction is a fundamental mechanism of organs maturation failure in premature infants. Data collected in support of this hypothesis are relevant to two major diseases of prematurity: white matter injury and broncho-pulmonary dysplasia. In these diseases, totally different clinical manifestations are defined by the same biological process, developmental failure of the main functional units-alveoli in the lungs and axonal myelination in the brain. Although molecular pathways regulating alveolar and white matter maturation differ, proper bioenergetic support of growth and maturation remains critical biological requirement for any actively developing organ. Literature analysis suggests that successful postnatal pulmonary and white matter development highly depends on mitochondrial function which can be inhibited by sublethal postnatal stress. In premature infants, sublethal stress results mostly in organ maturation failure without excessive cellular demise.

Figure 1

Electron microscopy of axons in the corpus callosum and H and E staining of lungs in the same mice treated with either vehicle or 2’4’ dinitrophenol (2 mcg/g). Scale bar: 1 µm (brain) and 50 µm (lungs).

Figure 2

Hypothetical mitochondria-driven mechanisms for postnatal developmental failure of lungs and cerebral white matter in premature infants.