Neural Plast. 2016;2016:3985063. doi: 10.1155/2016/3985063.

Linking Mitochondria to Synapses: New Insights for Stress-Related Neuropsychiatric Disorders.

Jeanneteau F1, Arango-Lievano M1.
  • 1Team AVENIR “Stress Hormones and Plasticity”, INSERM U1191, CNRS UMR5203, Institut de Génomique Fonctionnelle, 34094 Montpellier, France.



The brain evolved cellular mechanisms for adapting synaptic function to energy supply. This is particularly evident when homeostasis is challenged by stress. Signaling loops between the mitochondria and synapses scale neuronal connectivity with bioenergetics capacity. A biphasic “inverted U-shape” response to the stress hormone glucocorticoids is demonstrated in mitochondria and at synapses, modulating neural plasticity and physiological responses. Low dose enhances neurotransmission, synaptic growth, mitochondrial functions, learning and memory whereas chronic, higher doses produce inhibition of these functions. The range of physiological effects by stress and glucocorticoid depends on the dose, duration and context at exposure. These criteria are met by neuronal activity, the circadian, stress-sensitive and ultradian, stress-insensitive modes of glucocorticoid secretion. A major hallmark of stress-related neuropsychiatric disorders is the disrupted glucocorticoid rhythms and tissue resistance to signaling with the glucocorticoid receptor (GR). GR resistance could result from the loss of context-dependent glucocorticoid signaling mediated by the downregulation of the activity-dependent neurotrophin BDNF. The coincidence of BDNF and GR signaling changes glucocorticoid-signaling output with consequences on mitochondrial respiration efficiency, synaptic plasticity and adaptive trajectories.

PMID: 26885402



Several studies provided a useful framework for a pathway underlying the establishment and progression of several neuropsychiatric disorders by the concomitant re-organization of synaptic territories and the dysfunction of mitochondria; but these two responses are often investigated separately. We reviewed the signaling loops between mitochondria and synapses that could fail in stress-related neuropsychiatric disorders in Neural Plast, 2016: p. 3985063 (Linking Mitochondria to Synapses: New Insights for Stress-Related Neuropsychiatric Disorders) [1].


There are limits to which mitochondria can support trains of neuronal network activity. For instance, repetitive discharges of excitation during epileptic seizures produce severe mitochondrial dysfunctions, eventually resulting in neuronal death [2]. Modeling experiments indicate that synaptic depotentiation is likely desirable to support neuronal survival when energetic stores are limited [3]. Therefore, negative feedback mechanisms may have evolved to suppress synaptic potentiation that would drain ATP stores upon high frequency stimulation. From the characterization of such mechanisms could emerge novel modulators of neuroplasticity to stress?


These protective mechanisms are driven by nuclear transcriptional programs evolved to limit cellular damages. One such transcriptional program for optimizing energy utilization with respect to synaptic connectivity and function is mediated by the receptors for glucocorticoid stress hormones.


Little is known about the glucocorticoid signaling loops between synapses and mitochondria that are critical for scaling neuronal connectivity with bioenergetics capacity [4]. Also, the functional plasticity of mitochondria in the context of stress is incompletely understood. One question remains whether mitochondrial dysfunction constitutes an early, modifiable target of disorders caused by stress.


Aberrant mitochondrial function and metabolite levels (e.g. ATP, superoxides, acetyl-CoA, succinyl-CoA, S-adenosyl-methionine (SAM), NAD+, ketoglutarate) have been documented in biopsies of patients suffering from stress-related mental disorders [5, 6]. This suggests that people harboring “low power” mitochondria could be more vulnerable to stress. Molecules, like creatine monohydrate, that enhance mitochondrial functions were shown to be beneficial in animal and human studies when co-administered with antidepressant treatments. However, other studies investigating the efficacy of antidepressant therapies for ameliorating mitochondrial functions in the brain provided mixed results.


Recent study using rats as model [7], discriminated the effects of a 3-week treatment with the antidepressant drugs fluoxetine (10 mg/kg) and desipramine (15 mg/kg) between mitochondrial function in the somatic compartment linked to protein assembly and genomic regulation and mitochondrial function in the synaptic compartment linked to ions homeostasis and neurotransmission. Subcellular fractionation techniques were applied to frozen cortical biopsies for isolating the somatic, light “pre-synaptic” and heavy “post-synaptic” fractions, thereby permitting the identification of selective antidepressant effects on metabolic modifications within subcellular compartments. These specific effects are (i) the enhancement of cytochrome oxidase activity in the somatic mitochondria and post-synaptic mitochondria; (ii) the decrease of malate, succinate dehydrogenase and glutamate-pyruvate transaminase activities of the pre-synaptic mitochondria. Consequently, fluoxetine and desipramine changed enzymatic activities involved in the Krebs’ cycle and glutamate metabolism at the pre-synaptic mitochondria while impacting the activity of the electron transport chain in the somatic and the post-synaptic mitochondria. These specific subcellular effects provide one explanation for interpreting the conflicting data previously reported.


The cell biologist view of these results is an enhancement of energy metabolism in somatic mitochondria after desipramine/ fluoxetine treatment as a response to the enhanced utilization of ATP upon neuronal activation in the post-synaptic compartment. This is in agreement with the roles of desipramine and fluoxetine respectively, to increase the concentrations of norepinephrine and serotonin in the synaptic cleft, thereby stimulating intracellular signaling via postsynaptic receptors, leading to higher energy requirements. In contrast, the activation of presynaptic autoreceptors for norepinephrine and serotonin are expected to inhibit neurotransmitter release, thereby reducing presynaptic demands for energy production.


This study is important because it provides a possible explanation for the conflicting data regarding the effect of antidepressants drugs on mitochondrial function. This explanation is that the presynaptic and postsynaptic mitochondria may not respond the same way to antidepressant drug treatment.


Figure 1 copieFigure 1: Desipramine and fluoxetine increase the levels of serotonin [5-HT] and norepinephrine [NE] in the synaptic cleft facilitating receptor signaling at the presynapse to block vesicular release of neurotransmitter and at the postsynapse and the nucleus for long lasting adaptive responses. Overtime, this may increase ATP utilization at the post-synapse and in the soma but may decrease ATP utilization at the presynapse thereby impacting ATP production by local networks of mitochondria. Such compartmented subcellular effects of antidepressants are detected at the level of mitochondrial enzymes like COX (cytochrome oxidase) involved in the electron transport chain, SDH (succinate dehydrogenase), MDH (malate dehydrogenase) and CS (citrate synthase) involved in the Krebs’ cycle, and GPT (glutamate-pyruvate transaminase) involved in amino acid metabolism.



  1. Jeanneteau, F. and M. Arango-Lievano, Linking Mitochondria to Synapses: New Insights for Stress-Related Neuropsychiatric Disorders. Neural Plast, 2016. 2016: p. 3985063.
  2. Tang, Y. and R.S. Zucker, Mitochondrial involvement in post-tetanic potentiation of synaptic transmission. Neuron, 1997. 18(3): p. 483-91.
  3. Harris, J.J., R. Jolivet, and D. Attwell, Synaptic energy use and supply. Neuron, 2012. 75(5): p. 762-77.
  4. Du, J., et al., Dynamic regulation of mitochondrial function by glucocorticoids. Proc Natl Acad Sci U S A, 2009. 106(9): p. 3543-8.
  5. Klinedinst, N.J. and W.T. Regenold, A mitochondrial bioenergetic basis of depression. J Bioenerg Biomembr, 2015. 47(1-2): p. 155-71.
  6. Streck, E.L., et al., Mitochondria and the central nervous system: searching for a pathophysiological basis of psychiatric disorders. Rev Bras Psiquiatr, 2014. 36(2): p. 156-67.
  7. Villa, R.F., et al., Effect of desipramine and fluoxetine on energy metabolism of cerebral mitochondria. Neuroscience, 2016.



Freddy Jeanneteau, PhD

Margarita Arango-Lievano, PhD

Institut de Génomique Fonctionnelle (IGF)

Institut national de la santé et de la recherche médicale (INSERM), U1191

Centre National de la recherche scientifique (CNRS), UMR5203

F-34094 Montpellier, France.



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