Chronic energy depletion due to iron deficiency impairs dendritic mitochondrial motility during hippocampal neuron development

Thomas W Bastian, William C. von Hohenberg, Michael K Georgieff, Lorene M Lanier

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)802-813
Number of pages12
JournalJournal of Neuroscience
Volume39
Issue number5
DOIs
StatePublished - Jan 30 2019

Fingerprint

Mitochondrial Dynamics
Deferoxamine
Iron
Neurons
Mitochondria
Quality Control
Adenosine Triphosphate
Mitochondrial Size
Gene Fusion
Chelating Agents
Growth
Dendrites
Neurodegenerative Diseases
Energy Metabolism
Axons
Respiration
Homeostasis
Brain
In Vitro Techniques

Keywords

  • Dendrite
  • Energy metabolism
  • Iron deficiency
  • Mitochondria dynamics
  • Mitochondria motility
  • Mitochondria trafficking

Cite this

Chronic energy depletion due to iron deficiency impairs dendritic mitochondrial motility during hippocampal neuron development. / Bastian, Thomas W; von Hohenberg, William C.; Georgieff, Michael K; Lanier, Lorene M.

In: Journal of Neuroscience, Vol. 39, No. 5, 30.01.2019, p. 802-813.

Research output: Contribution to journalArticle

@article{956b98ae22e14ee4857e6808838bea47,
title = "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.",
keywords = "Dendrite, Energy metabolism, Iron deficiency, Mitochondria dynamics, Mitochondria motility, Mitochondria trafficking",
author = "Bastian, {Thomas W} and {von Hohenberg}, {William C.} and Georgieff, {Michael K} and Lanier, {Lorene M}",
year = "2019",
month = "1",
day = "30",
doi = "10.1523/JNEUROSCI.1504-18.2018",
language = "English (US)",
volume = "39",
pages = "802--813",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "5",

}

TY - JOUR

T1 - Chronic energy depletion due to iron deficiency impairs dendritic mitochondrial motility during hippocampal neuron development

AU - Bastian, Thomas W

AU - von Hohenberg, William C.

AU - Georgieff, Michael K

AU - Lanier, Lorene M

PY - 2019/1/30

Y1 - 2019/1/30

N2 - 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.

AB - 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.

KW - Dendrite

KW - Energy metabolism

KW - Iron deficiency

KW - Mitochondria dynamics

KW - Mitochondria motility

KW - Mitochondria trafficking

UR - http://www.scopus.com/inward/record.url?scp=85060930457&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85060930457&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.1504-18.2018

DO - 10.1523/JNEUROSCI.1504-18.2018

M3 - Article

VL - 39

SP - 802

EP - 813

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 5

ER -