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The oligosaccharide portion of ganglioside GM1 regulates mitochondrial function in neuroblastoma cells

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Abstract

The crucial role of ganglioside GM1 in the regulation of neural homeostasis has been assessed by several studies. Recently we shed new light on the molecular basis underlying GM1 effects demonstrating that GM1 oligosaccharide directly binds TrkA receptor and triggers MAPK pathway activation leading to neuronal differentiation and protection. Following its exogenous administration, proteomic analysis revealed an increased expression of proteins involved in several biochemical mechanisms, including mitochondrial bioenergetics. Based on these data, we investigated the possible effect of GM1 oligosaccharide administration on mitochondrial function. We show that wild-type Neuro2a cells exposed to GM1 oligosaccharide displayed an increased mitochondrial density and an enhanced mitochondrial activity together with reduced reactive oxygen species levels. Interestingly, using a Neuro2a model of mitochondrial dysfunction, we found an increased mitochondrial oxygen consumption rate as well as increased complex I and II activities upon GM1 oligosaccharide administration. Taken together, our data identify GM1 oligosaccharide as a mitochondrial regulator that by acting at the plasma membrane level triggers biochemical signaling pathway inducing mitochondriogenesis and increasing mitochondrial activity. Although further studies are necessary, the capability to enhance the function of impaired mitochondria points to the therapeutic potential of the GM1 oligosaccharide for the treatment of pathologies where these organelles are compromised, including Parkinson’s disease.

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Abbreviations

BSA:

Bovine serum albumin

CCCP:

Carbonyl cyanide 3-chlorophenylhydrazone

CTRL:

Control

DMEM:

Dulbecco’s modified Eagles’ medium

ERK1/2:

Extracellular signal-regulated protein kinases 1 and 2

ETC:

Electron transport chain

EtBr:

Ethidium bromide

FBS:

Fetal bovine serum

GM1:

II3Neu5Ac-Gg4Cer, β-Gal-(1–3)-β-GalNAc-(1–4)-[α-Neu5Ac-(2–3)]-β-Gal-(1–4)-β-Glc-Cer

HRP:

Horseradish peroxidase

MAPK:

Mitogen-activated protein kinase

mtDNA:

Mitochondrial DNA

MPP+ :

1-methyl-4-phenylpyridinium

MPTP:

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride

N2a:

Neuro2a cells

NGF:

Nerve growth factor

OligoGM1:

GM1 oligosaccharide, II3Neu5Ac-Gg4, β-Gal-(1–3)-β-GalNAc-(1–4)-[α-Neu5Ac-(2–3)]-β-Gal-(1–4)-Glc

Oxphos:

Oxidative phosphorylation

OCR:

Oxygen Consumption Rate

PBS:

Phosphate-buffered saline

PD:

Parkinson’s disease

PVDF:

Polyvinylidene difluoride

RRID:

Research resource identifiers

ROS:

Reactive oxygen species

TBS-T:

Tris-buffered saline containing 0.1% Tween-20

Trk:

Neurotrophin tyrosin kinase receptor

TEM:

Transmission electron microscopy

WT:

Wild-type

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Acknowledgments

This work was supported by University of Milano departmental funds RV_TAR16SSONN_M to SS and Fond PSR2017_RONDELLI-CHIRICOZZI to EC, by Intramural Transition Grant from the University of Milano to NM.

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Author notes

  1. Maria Fazzari and Matteo Audano contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Biotechnology and Translational Medicine, University of Milano, Via Fratelli Cervi 93, 20090, Segrate (MI), Italy

    Maria Fazzari, Giulia Lunghi, Erika Di Biase, Nicoletta Loberto, Laura Mauri, Sandro Sonnino & Elena Chiricozzi

  2. Department of Pharmacological and Biomolecular Sciences, University of Milano, Via Balzaretti 9, 20133, Milan (MI), Italy

    Matteo Audano & Nico Mitro

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  1. Maria Fazzari
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Fazzari, M., Audano, M., Lunghi, G. et al. The oligosaccharide portion of ganglioside GM1 regulates mitochondrial function in neuroblastoma cells. Glycoconj J 37, 293–306 (2020). https://doi.org/10.1007/s10719-020-09920-4

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  • DOI: https://doi.org/10.1007/s10719-020-09920-4

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