Mitochondrial Dysfunction and Permeability Transition in Neonatal Brain and Lung Injuries

Abstract

This review discusses the potential mechanistic role of abnormally elevated mitochondrial proton leak and mitochondrial bioenergetic dysfunction in the pathogenesis of neonatal brain and lung injuries associated with premature birth. Providing supporting evidence, we hypothesized that mitochondrial dysfunction contributes to postnatal alveolar developmental arrest in bronchopulmonary dysplasia (BPD) and cerebral myelination failure in diffuse white matter injury (WMI). This review also analyzes data on mitochondrial dysfunction triggered by activation of mitochondrial permeability transition pore(s) (mPTP) during the evolution of perinatal hypoxic-ischemic encephalopathy. While the still cryptic molecular identity of mPTP continues to be a subject for extensive basic science research efforts, the translational significance of mitochondrial proton leak received less scientific attention, especially in diseases of the developing organs. This review is focused on the potential mechanistic relevance of mPTP and mitochondrial dysfunction to neonatal diseases driven by developmental failure of organ maturation or by acute ischemia-reperfusion insult during development.

Keywords: brain; lungs; mitochondria; prematurity; proton leak.

Figure 1

Schematic presentation of hypothetical roles of mPTP in various cellular fates after HI insult in the developing brain: full recovery and survival, death or survival but at the expense of maturation/differentiation failure. Based on current literature, we propose that in the developing brain, CypD-independent (ANT? ATPase? dependent) mPTP activation initiates secondary energy failure and cellular death, while CypD-dependent mitochondrial ion/proton leak promotes cellular viability following cell-lethal HI insult [47]. However, the same CypD-dependent mitochondrial proton/ion leak, via uncoupling of mitochondrial respiration in differentiating oligodendrocytes contributes to their maturation failure to reach myelin-producing stage leading to diffuse white matter hypomyelination [40]. Thus, it is possible that in the developing brain HI injury CypD-independent mPTP contributes to cellular degeneration and CypD-dependent proton leak supports cellular viability but contributes to the post-HI maturation failure of viable/survived cells.