Synergistic Action of Dendritic Mitochondria and Creatine Kinase Maintains ATP Homeostasis and Actin Dynamics in Growing Neuronal Dendrites

Fukumitsu, Kansai; Fujishima, Kazuto; Yoshimura, Azumi; Wu, You Kure; Heuser, John E.; Kengaku, Mineko

doi:10.1523/jneurosci.4115-14.2015

Cited by 69 publications

(71 citation statements)

References 75 publications

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“…Taken together, the PS1 P117L AD neurons reproduce major characteristics observed in neurons in AD brain, and are useful for understanding molecular mechanisms of AD pathology in neurons. Many studies have shown the role of mitochondria on neuritogenesis through calcium handling and ATP production4344. Recently, we demonstrated that 8-oxoG accumulation in neuronal mtDNA results in mitochondrial dysfunction, and leads to poor neurite outgrowth with decreased complexity of neuritic arborization, using isolated cortical neurons from mice lacking both 8-oxo-dGTP-depleting MTH1 and 8-oxoG excising OGG130, similar to the AD model neurons.…”

Section: Discussionmentioning

confidence: 81%

Human mitochondrial transcriptional factor A breaks the mitochondria-mediated vicious cycle in Alzheimer’s disease

Oka

Leon

Sakumi

et al. 2016

Sci Rep

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In the mitochondria-mediated vicious cycle of Alzheimer’s disease (AD), intracellular amyloid β (Aβ) induces mitochondrial dysfunction and reactive oxygen species, which further accelerate Aβ accumulation. This vicious cycle is thought to play a pivotal role in the development of AD, although the molecular mechanism remains unclear. Here, we examined the effects of human mitochondrial transcriptional factor A (hTFAM) on the pathology of a mouse model of AD (3xTg-AD), because TFAM is known to protect mitochondria from oxidative stress through maintenance of mitochondrial DNA (mtDNA). Expression of hTFAM significantly improved cognitive function, reducing accumulation of both 8-oxoguanine, an oxidized form of guanine, in mtDNA and intracellular Aβ in 3xTg-AD mice and increasing expression of transthyretin, known to inhibit Aβ aggregation. Next, we found that AD model neurons derived from human induced pluripotent stem cells carrying a mutant PSEN1(P117L) gene, exhibited mitochondrial dysfunction, accumulation of 8-oxoguanine and single-strand breaks in mtDNA, and impaired neuritogenesis with a decreased expression of transthyretin, which is known to be downregulated by oxidative stress. Extracellular treatment with recombinant hTFAM effectively suppressed these deleterious outcomes. Moreover, the treatment increased expression of transthyretin, accompanied by reduction of intracellular Aβ. These results provide new insights into potential novel therapeutic targets.

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Section: Discussionmentioning

confidence: 81%

Human mitochondrial transcriptional factor A breaks the mitochondria-mediated vicious cycle in Alzheimer’s disease

Oka

Leon

Sakumi

et al. 2016

Sci Rep

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“…The importance of Cr in brain development has been highlighted in a recent study showing that the loss of Cr kinase leads to aberrant neuronal development. 35 In addition, maternal Cr supplementation in rats enhanced hippocampal neuron development and improved long-term potentiation. 36 Taken together, these data suggest that using Nestin-cre mice to generate brain-specific Slc6a8 disruption is more comparable to the ubiquitous Slc6a8 −/y mice.…”

Section: Discussionmentioning

confidence: 99%

Cognitive deficits and increases in creatine precursors in a brain‐specific knockout of the creatine transporter gene Slc6a8

Udobi

Kokenge

Hautman

et al. 2018

Genes Brain and Behavior

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Creatine transporter (CrT; SLC6A8) deficiency (CTD) is an X-linked disorder characterized by severe cognitive deficits, impairments in language and an absence of brain creatine (Cr). In a previous study, we generated floxed Slc6a8 (Slc6a8 ) mice to create ubiquitous Slc6a8 knockout (Slc6a8 ) mice. Slc6a8 mice lacked whole body Cr and exhibited cognitive deficits. While Slc6a8 mice have a similar biochemical phenotype to CTD patients, they also showed a reduction in size and reductions in swim speed that may have contributed to the observed deficits. To address this, we created brain-specific Slc6a8 knockout (bKO) mice by crossing Slc6a8 mice with Nestin-cre mice. bKO mice had reduced cerebral Cr levels while maintaining normal Cr levels in peripheral tissue. Interestingly, brain concentrations of the Cr synthesis precursor guanidinoacetic acid were increased in bKO mice. bKO mice had longer latencies and path lengths in the Morris water maze, without reductions in swim speed. In accordance with data from Slc6a8 mice, bKO mice showed deficits in novel object recognition as well as contextual and cued fear conditioning. bKO mice were also hyperactive, in contrast with data from the Slc6a8 mice. The results show that the loss of cerebral Cr is responsible for the learning and memory deficits seen in ubiquitous Slc6a8 mice.

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“…Cell intrinsically, mitochondrial respiration and energy metabolism is a potential candidate, as mitochondrial function is directly dependent on iron and is also critical for dendrite growth [9]. Abnormalities in hippocampal energy metabolism have been documented in the IDA rat while iron-deficient [13,24,56] and in adulthood long after iron repletion [57].…”

Section: Discussionmentioning

confidence: 99%

Iron Deficiency Impairs Developing Hippocampal Neuron Gene Expression, Energy Metabolism, and Dendrite Complexity

et al. 2016

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Iron deficiency (ID), with and without anemia, affects an estimated 2 billion people worldwide. ID is particularly deleterious during early-life brain development, leading to long-term neurological impairments including deficits in hippocampus-mediated learning and memory. Neonatal rats with fetal/neonatal ID anemia (IDA) have shorter hippocampal CA1 apical dendrites with disorganized branching. ID-induced dendritic structural abnormalities persist into adulthood despite normalization of the iron status. However, the specific developmental effects of neuronal iron loss on hippocampal neuron dendrite growth and branching are unknown. Embryonic hippocampal neuron cultures were chronically treated with deferoxamine (DFO, an iron chelator) beginning at 3 days in vitro (DIV). Levels of mRNA for Tfr1 and Slc11a2, iron-responsive genes involved in iron uptake, were significantly elevated in DFO-treated cultures at 11DIV and 18DIV, indicating a degree of neuronal ID similar to that seen in rodent ID models. DFO treatment decreased mRNA levels for genes indexing dendritic and synaptic development (i.e. BdnfVI,Camk2a,Vamp1,Psd95,Cfl1, Pfn1,Pfn2, and Gda) and mitochondrial function (i.e. Ucp2,Pink1, and Cox6a1). At 18DIV, DFO reduced key aspects of energy metabolism including basal respiration, maximal respiration, spare respiratory capacity, ATP production, and glycolytic rate, capacity, and reserve. Sholl analysis revealed a significant decrease in distal dendritic complexity in DFO-treated neurons at both 11DIV and 18DIV. At 11DIV, the length of primary dendrites and the number and length of branches in DFO-treated neurons were reduced. By 18DIV, partial recovery of the dendritic branch number in DFO-treated neurons was counteracted by a significant reduction in the number and length of primary dendrites and the length of branches. Our findings suggest that early neuronal iron loss, at least partially driven through altered mitochondrial function and neuronal energy metabolism, is responsible for the effects of fetal/neonatal ID and IDA on hippocampal neuron dendritic and synaptic maturation. Impairments in these neurodevelopmental processes likely underlie the negative impact of early life ID and IDA on hippocampus-mediated learning and memory.

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Synergistic Action of Dendritic Mitochondria and Creatine Kinase Maintains ATP Homeostasis and Actin Dynamics in Growing Neuronal Dendrites

Cited by 69 publications

References 75 publications

Human mitochondrial transcriptional factor A breaks the mitochondria-mediated vicious cycle in Alzheimer’s disease

Human mitochondrial transcriptional factor A breaks the mitochondria-mediated vicious cycle in Alzheimer’s disease

Cognitive deficits and increases in creatine precursors in a brain‐specific knockout of the creatine transporter gene Slc6a8

Iron Deficiency Impairs Developing Hippocampal Neuron Gene Expression, Energy Metabolism, and Dendrite Complexity

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