Iron deficiency (ID), with and without anemia affects an estimated 2 billion people including 40% of pregnant women. ID is particularly deleterious during early-life brain development, leading to significant neurological impairments in children (e.g. learning and memory deficits). More troubling is that the learning and memory impairments persist into adulthood despite iron treatment in infancy, implying that iron therapy alone is not sufficient for full recovery. Thus, the long-term effects of lost education and job potential are te real cost to society of early-life ID. Understanding the iron-dependent molecular/cellular mechanisms that directly cause neurological dysfunction will allow future design of more effective therapies to prevent the long-lasting effects. The newborn brain is highly metabolic, accounting for 60% of total body oxygen consumption. Iron provides the catalytic component for several mitochondrial enzymes required for energy (ATP) production. Early-life ID reduces the energy status of the developing hippocampus, a highly metabolic brain region important for learning and memory. Early-life ID also impairs hippocampal neuron maturation, a metabolically demanding process, leading to reduced dendritic complexity and blunted spine formation in adulthood despite normalization of iron status. However, the molecular/cellular mechanisms contributing to the hippocampal energy impairments and how impaired energy status causes long-term neuronal structural deficits following developmental ID remain unclear. I will test the hypothesis that impaired mitochondrial respiration causes reduced energy status, leading to structural abnormalities in developing iron-deficient and mature formerly iron- deficient mouse hippocampal neurons. I will address this hypothesis through two specific aims.
In Aim 1, I will determine the effect of ID on mitochondrial respiration and intracellular trafficking in developing hippocampal neurons. Key parameters of mitochondrial oxidative phosphorylation and glycolysis and mitochondrial recruitment to growing dendrites/spines will be measured in iron-sufficient and -deficient hippocampal neurons.
In Aim 2, I will test whether restoring energy status in addition to iron repletion attenuates the acute and chronic neuronal structural deficits f developmental ID. Select steps of energy metabolism will be genetically or pharmacologically manipulated in cultured mouse hippocampal neurons, with or without iron repletion, and dendrite complexity and dendritic spine density and morphology will be assessed. This proposal is significant because it defines the role of specific energy metabolic processes in normal neuronal development and determines how a clinically relevant level of ID compromises them, thus providing a mechanistic basis for energy-specific therapies for fetal/neonatal ID. These discoveries and my professional and technical training in neuronal live-cell microscopy, morphology analysis and cellular bioenergetics will form the basis for an independent research career studying nutritional-metabolic regulation of neurodevelopment.
Iron deficiency affects approximately 2 billion people worldwide and causes significant neurobehavioral abnormalities in children (e.g. learning and memory deficits). These persist into adulthood despite iron repletion, thus constituting the real cost to society in terms of education and job potential loss. An understanding of the responsible cellular mechanisms is necessary in order to develop more effective therapies that prevent the long-lasting effects. This proposal tests the hypothesis that reduced neuronal energy status and mitochondrial function early in life forms the mechanistic basis for the blunted neuronal maturation observed in the hippocampus following iron deficiency during development.
| Bastian, T W; Duck, K A; Michalopoulos, G C et al. (2017) Eltrombopag, a thrombopoietin mimetic, crosses the blood-brain barrier and impairs iron-dependent hippocampal neuron dendrite development. J Thromb Haemost 15:565-574 |
