The control of dendritic branching by mitochondria

The control of dendritic branching by mitochondria
Complex dendritic trees. Credit:

(Medical Xpress)—A fundamental difference between neurons in real brains and those in artificial neural networks is the way the neurons in each are connected. In artificial nets, the synapses between neurons often have adjustable strengths, but the structure and scale of the input dendritic field generally counts for little. For real neurons, where a "connection" between cells is not just a synapse but rather a whole net unto itself, structure and scale are everything. The architect of this dendritic structure is neither a DNA code nor a spontaneous developmental physics that condenses order from a protein-lipid chaos. This structure is in fact the byproduct of competitive, yet cooperative mitochondria that administer that code to themselves and to their host to control its interaction with other similarly controlled hosts.

Reseachers from Osaku University have found that if are depleted from developing in pyramidal cells, there is increased branching in the proximal region of the dendrites. In their paper last week in the Journal of Neuroscience, they also show that these dendrites grow longer. Since mitochondria distribute not just energy but also metabolites, proteins, and mRNAs throughout the cell, these results may be somewhat surprising. However depending on what manipulations have been done to alter the mitochondria, many things might be expected to happen to dendrites and the cell in general.

Previous reports have shown that eliminating mitochondria from dendrites of mitofusion-2 null Purkinje cells results in a reduction in dendrite number. Other studies in cultured hippocampal neurons found no alterations in branch patterns. The present study achieved depletion of mitochondria from dendrites by altering similar mitofusion (Mfn) proteins. In this case Mfn-1 was overexpressed, essentially initiating a massive mitochondrial fusion fest. This subsequently confines them to the soma. The authors were also able to achieve the same effects on dendrites by overexpressing TRAK2. This is a truncated form of a motor-adapter protein which would presumably interfere with transport along the cytoskeleton.

The control of dendritic branching by mitochondria
Credit: Santiago Ramón y Cajal

The authors suggest that a main difference with their new study may be that for the prior Purkinje cell experiments the dendrites were already developed, while here the mitochondria were perturbed at the outset. They offer three mechanisms—ATP generation, Ca2 buffering, and caspase activation—towards an explanation of their observed effects, which unfortunately, they tend to simplify as being either "positive or negative dendritic regulation."

For all we know, the behavior of mitochondria that have congealed into a synticium may be as different from the dispersed state as is the slime-mold from the individual free-roaming amoeboids, or from the radicalized hormone-crazed locust swarm from peaceable lone foragers. Imaging the fast contractions and depolarizations of individual mitochondria may now give more clues as to what they are doing then any given handfull of molecular indicators, but such studies have not yet been done in the fused state, if we may even call it that.

To return to the opening remarks regarding networks, we might reasonably assume that a fundamental principle used by real brains but ignored in the artificial, is that when one neuron wants to talk to another it uses an expansive net to do it. Similarly, a related principle would be that at increasing scales (neurite lengths and distances between cells) dendro-dendro connected neurons using graded potentials turn into directionally polarized axo-dendritic units that speak with spikes. If we accept that spikes are typically evoked from a proximal axon spike generator then this effectively yields more power to the centralized, and by default, synchronizing soma.

The role of mitochondria in controlling local structures like spines has been known for some time. An understanding of their control of the gross structure of dendritic or axonal trees is now only at the theoretical state. A better grasp of these effects can give insight not just into individual cells, but whole systems of the brain. A cetacean brain, for example, may have become numbed over evolutionary time to the slow olfactory or gustatory senses that might benefit from the more deliberating integrative properties of the long apical dendrites that would be afforded by a thick cortex. A thin but expansive cortex on the other hand, with small dendrites, fast processing times, and correspondingly more deep layer output cells may be ideal in echolocation.

Nearly every day brings new understanding of the effects of individual mitochondrial-associated proteins on neurons and their diseases. Earlier this week for example, we saw how the accumulation in mitochondria of Huntingtin, a protein critical in Huntington's disease, leads to problems for the cell. As these novel mechanisms are clothed in ever greater molecular detail, it is important to keep the big picture in mind at the same time to wring all that we might from these experiments.

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Fast contractions and depolarizations in mitochondria revealed with multiparametric imaging

More information: Evidence That Dendritic Mitochondria Negatively Regulate Dendritic Branching in Pyramidal Neurons in the Neocortex, The Journal of Neuroscience, 14 May 2014, 34(20): 6938-6951; DOI: 10.1523/JNEUROSCI.5095-13.2014 ,

The precise branching patterns of dendritic arbors have a profound impact on information processing in individual neurons and the brain. These patterns are established by positive and negative regulation of the dendritic branching. Although the mechanisms for positive regulation have been extensively investigated, little is known about those for negative regulation. Here, we present evidence that mitochondria located in developing dendrites are involved in the negative regulation of dendritic branching. We visualized mitochondria in pyramidal neurons of the mouse neocortex during dendritic morphogenesis using in utero electroporation of a mitochondria-targeted fluorescent construct. We altered the mitochondrial distribution in vivo by overexpressing Mfn1, a mitochondrial shaping protein, or the Miro-binding domain of TRAK2 (TRAK2-MBD), a truncated form of a motor-adaptor protein. We found that dendritic mitochondria were preferentially targeted to the proximal portion of dendrites only during dendritic morphogenesis. Overexpression of Mfn1 or TRAK2-MBD depleted mitochondria from the dendrites, an effect that was accompanied by increased branching of the proximal portion of the dendrites. This dendritic abnormality cannot be accounted for by changes in the distribution of membrane trafficking organelles since the overexpression of Mfn1 did not alter the distributions of the endoplasmic reticulum, Golgi, or endosomes. Additionally, neither did these constructs impair neuronal viability or mitochondrial function. Therefore, our results suggest that dendritic mitochondria play a critical role in the establishment of the precise branching pattern of dendritic arbors by negatively affecting dendritic branching.

Journal information: Journal of Neuroscience

© 2014

Citation: The control of dendritic branching by mitochondria (2014, May 22) retrieved 20 July 2019 from
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May 22, 2014
@John Hewitt

Something has gone wrong with my browsers that seems to prevent my comments on your articles. I came in through a link from the title of this article.

I wonder if Ed Boyden might be having the same difficulty. Thanks for encouraging discussion of the epigenetic link from nutrient uptake to mitochondrial regulation of metabolism and cell type differentiation including the differentiation that leads to neurogenic niche construction -- as reported by Ed's group.

But, I think that few people grasp the fact that conserved molecular mechanisms are involved in species from microbes to man. Most seem capable only of thinking in terms of mutation-initiated natural selection and are pitifully uneducable.

May 22, 2014
Once again even the exploration of mechanisms of neuroscience are hampered by a model of neural networks based upon a simple on off base 2 computer code architecture. This appears also in attempt to reduce the DNA code. We are finding out that an approach much closer to gestalt in psychology is sorely needed.

May 22, 2014
Thanks for the comments. Although some studies seem to indicate neurites/axon can persist for a while without mitochondria, it seems that spines make perfect cell block incubator proving grounds for them, providing one clue as to why Cajal's retina nets, for example, use so many perfectly sized synapses instead of moving to bigger, but fewer (endbulb of held) type synapses. just food for thought

May 22, 2014
Re: on off computer codes and food odors for thought:

"One of the main duplicated gene families are the olfactory receptor proteins [18,117–119] so perhaps their duplication may lead to an increase in sensitivity to a particular odour may be adaptive under certain conditions." http://rspb.royal...abstract

This ecological adaptation precedes any others in my model and it can be viewed in the context of the conserved molecular mechanisms that link ecological variation in nutrient availability in yeasts to:

Epigenetic Variance Guides Interpretation of Natural Human Variation

Kondrashov is also co-author on that claims "The origins of neural systems remain unresolved." -- as if Ed Boyden's group was not aware of where nutrient-dependent neural systems come from.

May 22, 2014
Good stuff. and timely. did membrane g-protein based receptors originate first for mechanotransduction, olfaction, vision, or immune functions I wonder and are the transduction systems continuous from that start point with the present day analogous systems used in higher species?

May 22, 2014
Self / non-self recognition requires the g-protein coupled receptor functions of the olfactory and the immune systems. Sensing and signaling systems in bacteria are linked to sex differences in cell types of yeasts to mammals in our 1996 review http://www.hawaii...ion.html via the conserved molecular mechanisms that have since been well-detailed across all species.

http://stke.scien...291/pe28 http://www.ncbi.n...16290036

May 23, 2014
I think that few people grasp the fact that conserved molecular mechanisms are involved in species from microbes to man. Most seem capable only of thinking in terms of mutation-initiated natural selection and are pitifully uneducable.

You think common descent contradicts natural selection? I am not able rightly to apprehend the kind of confusion of ideas that could provoke such a statement.

May 23, 2014
You think common descent contradicts natural selection? I am not able rightly to apprehend the kind of confusion of ideas that could provoke such a statement.

That's not all. Over on this article, he seems to think reproduction (sexual selection) and natural selection are opposing and incompatible processes:


May 23, 2014
I wrote: "Random change followed by selection cannot occur in the absence of nutrient-dependent pheromone-controlled reproduction, which makes mutation-initiated natural selection a ridiculous proposal in the context of everything currently known about the biophysical constraints on biodiversity.

Only idiots remain to comment on experimental evidence presented here. I give up!"

Now, the anonymous fool shows up again to derail intelligent discussion about natural selection for food, and try to link mutations and natural selection for something else to nutrient-dependent pheromone-controlled reproduction and species diversity via amino acid substitutions in species from microbes to man.

Nutrient-dependent/pheromone-controlled adaptive evolution: a model

The problem is that I have detailed how natural selection for food and sexual selection for morphological and behavioral traits actually occurs, and fools don't know what is selected.

May 23, 2014
natural selection for something else

I love how you act as though you haven't been told about this dozens of times. Natural selection is for advantageous phenotypes. Brown bears are pretty conspicuous in the snow, which is why those that got mutations preventing pigment synthesis were able to move north and fill an empty niche.

May 24, 2014
The egg bearers, in our case the homozygous sex chromosomed ones, appear to be the primary selector of desirable traits, as opposed to some than some confounded survival process accounting for evolution

May 24, 2014
Brown bears made themselves white in a process that I would not call any more random then the sun is found to result in a tan or a even a cuttlefish toggle its pigments in real time. The built in mechanisms of adaptions are difficult to see perhaps, but none-the-less they are there.

May 24, 2014
The built in mechanisms of adaptions are difficult to see perhaps, but none-the-less they are there.
-- Hewitt (2014)

Thanks John. Unfortunately, anonymous_9001 cannot comprehend biological facts!

"The notion has gained some currency that the only worthwhile biology is molecular biology." -- Dobzhansky (1964)

"Reproductive isolation evidently can arise with little or no morphological differentiation." -- Dobzhansky (1972)

"...alpha chains of hemoglobin have identical sequences of amino acids in man and the chimpanzee, but they differ in a single amino acid (out of 141) in the gorilla." - Dobzhansky (1973)

Indeed, no matter how many times others are told that amino acid substitutions are not mutations, most people cannot think in terms of how ecological variation leads to ecological adaptations via biophysically constrained substitutions. They attribute everything to mutations long after Dobzhansky implied they were bird-watchers and butterfly-collectors who saw nothing.

May 27, 2014
Well I suppose one could say heat/thermal motion is a mechanism of biodiversity if they really want, but it is getting old having to listen to the big name sci writers always retreating to blind mutation + nat selection as the engine of reality. Anon. makes reasonable points too though so lets get along here. I am interested in better defining how genomes progress from through predictable mutations (radiation-induced, spontaneous or whatever) to final, perhaps more stable forms if we might call it that. Things like birds/high metabolizers having predictable GC content or favored sequences, etc.

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