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Translational control of mitochondrial energy production mediates neuron morphogenesis.

ABSTRACT: Mitochondrial energy production is a tightly regulated process involving the coordinated transcription of several genes, catalysis of a plethora of posttranslational modifications, and the formation of very large molecular supercomplexes. The regulation of mitochondrial activity is particularly important for the brain, which is a high-energy-consuming organ that depends on oxidative phosphorylation to generate ATP. Here we show that brain mitochondrial ATP production is controlled by the cytoplasmic polyadenylation-induced translation of an mRNA encoding NDUFV2, a key mitochondrial protein. Knockout mice lacking the Cytoplasmic Polyadenylation Element Binding protein 1 (CPEB1) have brain-specific dysfunctional mitochondria and reduced ATP levels, which is due to defective polyadenylation-induced translation of electron transport chain complex I protein NDUFV2 mRNA. This reduced ATP results in defective dendrite morphogenesis of hippocampal neurons both in vitro and in vivo. These and other results demonstrate that CPEB1 control of mitochondrial activity is essential for normal brain development.

SUBMITTER: Oruganty-Das A

PROVIDER: S-EPMC3597101 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Translational control of mitochondrial energy production mediates neuron morphogenesis.

Oruganty-Das Aparna A Ng Teclise T Udagawa Tsuyoshi T Goh Eyleen L K EL Richter Joel D JD

Cell metabolism 20121201 6

Mitochondrial energy production is a tightly regulated process involving the coordinated transcription of several genes, catalysis of a plethora of posttranslational modifications, and the formation of very large molecular supercomplexes. The regulation of mitochondrial activity is particularly important for the brain, which is a high-energy-consuming organ that depends on oxidative phosphorylation to generate ATP. Here we show that brain mitochondrial ATP production is controlled by the cytopla ...[more]

PMID: 23217258

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Project description:Proper neural function depends on the correct specification of individual neural fates, controlled by combinations of neuronal transcription factors. Different neural types are sequentially generated by neural progenitors in a defined order, and this temporal patterning process can be controlled by Temporal Transcription Factors (TTFs) that form temporal cascades in neural progenitors. The Drosophila medulla, part of the visual processing center of the brain, contains more than 70 neural types generated by medulla neuroblasts which sequentially express several TTFs, including Homothorax (Hth), eyeless (Ey), Sloppy paired 1 and 2 (Slp), Dichaete (D) and Tailless (Tll). However, it is not clear how such a small number of TTFs could give rise to diverse combinations of neuronal transcription factors that specify a large number of medulla neuron types. Here we report how temporal patterning specifies one neural type, the T1 neuron. We show that the T1 neuron is the only medulla neuron type that expresses the combination of three transcription factors Ocelliless (Oc or Otd), Sox102F and Ets65A. Using CRISPR-Cas9 system, we show that each transcription factor is required for the correct morphogenesis of T1 neurons. Interestingly, Oc, Sox102F and Ets65A initiate expression in neurons beginning at different temporal stages and last in a few subsequent temporal stages. Oc expressing neurons are generated in the Ey, Slp and D stages; Sox102F expressing neurons are produced in the Slp and D stages; while Ets65A is expressed in subsets of medulla neurons born in the D and later stages. The TTF Ey, Slp or D is required to initiate the expression of Oc, Sox102F or Ets65A in neurons, respectively. Thus, the neurons expressing all three transcription factors are born in the D stage and become T1 neurons. In neurons where the three transcription factors do not overlap, each of the three transcription factors can act in combination with other neuronal transcription factors to specify different neural fates. We show that this way of expression regulation of neuronal transcription factors by temporal patterning can generate more possible combinations of transcription factors in neural progeny to diversify neural fates.

Project description: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.SIGNIFICANCE STATEMENT 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.

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Translational control of mitochondrial energy production mediates neuron morphogenesis.

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Translational control of mitochondrial energy production mediates neuron morphogenesis.

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