Chronic Energy Depletion due to Iron Deficiency Impairs Dendritic Mitochondrial Motility during Hippocampal Neuron Development

Abstract

During development, neurons require highly integrated metabolic machinery to meet the large energy demands of growth, differentiation, and synaptic activity within their complex cellular architecture. Dendrites/axons require anterograde trafficking of mitochondria for local ATP synthesis to support these processes. Acute energy depletion impairs mitochondrial dynamics, but how chronic energy insufficiency affects mitochondrial trafficking and quality control during neuronal development is unknown. Because iron deficiency impairs mitochondrial respiration/ATP production, we treated mixed-sex embryonic mouse hippocampal neuron cultures with the iron chelator deferoxamine (DFO) to model chronic energetic insufficiency and its effects on mitochondrial dynamics during neuronal development. At 11 days in vitro (DIV), DFO reduced average mitochondrial speed by increasing the pause frequency of individual dendritic mitochondria. Time spent in anterograde motion was reduced; retrograde motion was spared. The average size of moving mitochondria was reduced, and the expression of fusion and fission genes was altered, indicating impaired mitochondrial quality control. Mitochondrial density was not altered, suggesting that respiratory capacity and not location is the key factor for mitochondrial regulation of early dendritic growth/branching. At 18 DIV, the overall density of mitochondria within terminal dendritic branches was reduced in DFO-treated neurons, which may contribute to the long-term deficits in connectivity and synaptic function following early-life iron deficiency. The study provides new insights into the cross-regulation between energy production and dendritic mitochondrial dynamics during neuronal development and may be particularly relevant to neuropsychiatric and neurodegenerative diseases, many of which are characterized by impaired brain iron homeostasis, energy metabolism and mitochondrial trafficking.This study uses a primary neuronal culture model of iron deficiency to address a gap in understanding of how dendritic mitochondrial dynamics are regulated when energy depletion occurs during a critical period of neuronal maturation. At the beginning of peak dendritic growth/branching, iron deficiency reduces mitochondrial speed through increased pause frequency, decreases mitochondrial size, and alters fusion/fission gene expression. At this stage, mitochondrial density in terminal dendrites is not altered, suggesting that total mitochondrial oxidative capacity and not trafficking is the main mechanism underlying dendritic complexity deficits in iron-deficient neurons. Our findings provide foundational support for future studies exploring the mechanistic role of developmental mitochondrial dysfunction in neurodevelopmental, psychiatric, and neurodegenerative disorders characterized by mitochondrial energy production and trafficking deficits.

Correlating STED and synchrotron XRF nano-imaging unveils cosegregation of metals and cytoskeleton proteins in dendrites

“…On the other hand, iron was observed as local hot spots of few hundred of nanometers along dendrites, the exact nature of these local iron-enrichment remains to be elucidated. A possible explanation could be the presence of iron in mitochondria known to be present in dendrites of hippocampal neurons ( Bastian et al, 2019 ).…”

Dysregulation of Neuronal Genes by Fetal-Neonatal Iron Deficiency Anemia Is Associated with Altered DNA Methylation in the Rat Hippocampus

“…It is localized in the endoplasmic reticulum and mitochondria [49] and is involved in the synthesis of phosphatidylglycerol and cardiolipin, an important component of the inner mitochondrial membrane [50]. Cds1 is a novel regulator of lipid droplet formation, lipid storage, and adipocyte development [51], and plays a critical role in mammalian energy storage, which is compromised in developing iron-deficient neurons [52].…”

Correlating STED and synchrotron XRF nano-imaging unveils the co-segregation of metals and cytoskeleton proteins in dendrites

“…On the other hand, iron was observed as local hot spots of few hundred of nanometers along dendrites, the exact nature of these local iron-enrichment remains to be elucidated. A possible explanation could be the presence of iron in mitochondria known to be present in dendrites of hippocampal neurons (Bastian et al, 2019). During manufacturing, a second, smaller (0.1 x 0.1 mm 2 ), SN membrane is added in one of the corners of the silicon frame to serve as orientation object.…”