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Nicotine Modulates Mitochondrial Dynamics in Hippocampal Neurons

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Abstract

Mitochondria are widely recognized as fundamental organelles for cellular physiology and constitute the main energy source for different cellular processes. The location, morphology, and interactions of mitochondria with other organelles, such as the endoplasmic reticulum (ER), have emerged as critical events capable of determining cellular fate. Mitochondria-related functions have proven particularly relevant in neurons; mitochondria are necessary for proper neuronal morphogenesis and the highly energy-demanding synaptic transmission process. Mitochondrial health depends on balanced fusion-fission events, termed mitochondrial dynamics, to repair damaged organelles and/or improve the quality of mitochondrial function, ATP production, calcium homeostasis, and apoptosis, which represent some mitochondrial functions closely related to mitochondrial dynamics. Several neurodegenerative disorders, such as Alzheimer’s, Parkinson’s, and Huntington’s diseases, have been correlated with severe mitochondrial dysfunction. In this regard, nicotine, which has been associated with relevant neuroprotective effects mainly through activation of the nicotinic acetylcholine receptor (nAChR), exerts its effects at least in part by acting directly on mitochondrial physiology and morphology. Additionally, a recent description of mitochondrial nAChR localization suggests a nicotine-dependent mitochondrial function. In the present work, we evaluated in cultured hipocampal neurons the effects of nicotine on mitochondrial dynamics by assessing mitochondrial morphology, membrane potential, as well as interactions between mitochondria, cytoskeleton and IP3R, levels of the cofactor PGC-1α, and fission-fusion-related proteins. Our results suggest that nicotine modulates mitochondrial dynamics and influences mitochondrial association from microtubules, increasing IP3 receptor clustering showing modulation between mitochondria-ER communications, together with the increase of mitochondrial biogenesis.

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Abbreviations

ATP:

adenosine triphosphate

AMPK:

AMP-activated protein kinase

ER:

endoplasmic reticulum

MFN2:

mitofusin 2

AraC:

cytosine arabinoside

PBS:

phosphate-buffered saline

PBSCAM:

phosphate-buffered saline/calcium magnesium

BSA:

bovine serum albumin

DIV:

days in vitro

SEM:

standard error of the mean

IP3R:

inositol 1,4,5-trisphosphate receptor

OPA1:

optic atrophy 1

DRP1:

dynamin-related protein 1

PGC-1α:

peroxisome proliferator-activated receptor γ co-activator 1α

ROS:

reactive oxygen species

mΔΨ:

mitochondrial membrane potential

α-Btx:

alpha-bungarotoxin

DHβE:

dihydro-β-erythroidine hydrobromide

CTCF:

corrected total cell fluorescence

nAChR:

nicotinic acetylcholine receptor

α7-AChR:

alpha7-nicotinic acetylcholine receptor

ACh:

acetylcholine

AD:

Alzheimer’s disease

Wnt:

Wingless/integration site

ETC:

electron transport chain

mCx-I:

mitochondrial complex I

MFN2:

mitofusin2

mPTP:

mitochondrial permeability transition pore

Mdivi-1:

mitochondrial division inhibitor 1

NADH:

nicotinamide adenine dinucleotide

Mt-cyb:

cytochrome b

MTs:

microtubules

RyR:

ryanodine receptor

SERCA:

sarco/endoplasmic reticulum Ca+2-ATPase

MIRO:

mitochondrial rho GTPase

TOM 20:

translocase of outer mitochondrial membrane 20

VDAC:

voltage-dependent anion channel

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Funding

This work was supported by grants AFB 170005 and CONICYT-PFB 12/2007 from the Basal Centre for Excellence in Science and Technology (CARE UC) and FONDECYT 1160724, both to NCI. JAG is a PhD student at Universitat Pompeu Fabra, Barcelona, Spain. AGV was supported by a Santander Río Ibero-American fellowship through UC and PICT-2015-1031 from the National Scientific and Technical Research Council of Argentina (CONICET).

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Author notes

  1. Juan A. Godoy and Angel G. Valdivieso contributed equally to this work.

Authors and Affiliations

  1. Centro de Envejecimiento y Regeneración (CARE UC); Departamento de Biología Celular y Molecular; Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile

    Juan A. Godoy & Nibaldo C. Inestrosa

  2. Centro de Excelencia en Biomedicina de Magallanes (CEBIMA), Universidad de Magallanes, Punta Arenas, Chile

    Juan A. Godoy & Nibaldo C. Inestrosa

  3. Institute for Biomedical Research (BIOMED), Laboratory of Cellular and Molecular Biology, School of Medical Sciences, Pontifical Catholic University of Argentina (UCA) and The National Scientific and Technical Research Council of Argentina (CONICET), Buenos Aires, Argentina

    Angel G. Valdivieso

  4. Centre for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, Australia

    Nibaldo C. Inestrosa

  5. (CARE UC) Biomedical Center, Pontificia Universidad Católica de Chile, Av. Libertador Bernardo O’Higgins, 340, Santiago, Chile

    Nibaldo C. Inestrosa

Authors
  1. Juan A. Godoy
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  2. Angel G. Valdivieso
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  3. Nibaldo C. Inestrosa
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Contributions

JAG conceived and conducted most of the experiments with mitochondria, analyzed the results and wrote most of the article. AGV conducted the western blot experiments, analyzed the results and wrote the article. NCI conceived the general idea for the project and wrote the article.

Corresponding author

Correspondence to Nibaldo C. Inestrosa.

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All authors declare no conflicts of interest related to the contents of this article.

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Godoy, J.A., Valdivieso, A.G. & Inestrosa, N.C. Nicotine Modulates Mitochondrial Dynamics in Hippocampal Neurons. Mol Neurobiol 55, 8965–8977 (2018). https://doi.org/10.1007/s12035-018-1034-8

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