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.
Bibliographical noteFunding Information:
This work was supported by National Institutes of Health Grants R01 HD029421 to M.K.G., R01 HD094809 to M.K.G., and F32 HD085576 to T.W.B. We thank Justin Campagna and Lanka Dasanayaka for invaluable assistance with culture preparation and image analysis. A portion of the live microscopic imaging was performed at the University Imaging Centers at the University of Minnesota. The authors declare no competing financial interests.
© 2019 the authors.
- Energy metabolism
- Iron deficiency
- Mitochondria dynamics
- Mitochondria motility
- Mitochondria trafficking