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Mitochondrial dysfunction in adult midbrain dopamine neurons triggers an early immune response

Filograna, Roberta ; Lee, Seungmin ; Tiklova, Katarina ; Mennuni, Mara ; Jonsson, Viktor ; Ringnér, Markus LU orcid ; Gillberg, Linda ; Sopova, Elena ; Shupliakov, Oleg and Koolmeister, Camilla , et al. (2021) In PLoS Genetics 17(9). p.1009822-1009822
Abstract

Dopamine (DA) neurons of the midbrain are at risk to become affected by mitochondrial damage over time and mitochondrial defects have been frequently reported in Parkinson's disease (PD) patients. However, the causal contribution of adult-onset mitochondrial dysfunction to PD remains uncertain. Here, we developed a mouse model lacking Mitofusin 2 (MFN2), a key regulator of mitochondrial network homeostasis, in adult midbrain DA neurons. The knockout mice develop severe and progressive DA neuron-specific mitochondrial dysfunction resulting in neurodegeneration and parkinsonism. To gain further insights into pathophysiological events, we performed transcriptomic analyses of isolated DA neurons and found that mitochondrial dysfunction... (More)

Dopamine (DA) neurons of the midbrain are at risk to become affected by mitochondrial damage over time and mitochondrial defects have been frequently reported in Parkinson's disease (PD) patients. However, the causal contribution of adult-onset mitochondrial dysfunction to PD remains uncertain. Here, we developed a mouse model lacking Mitofusin 2 (MFN2), a key regulator of mitochondrial network homeostasis, in adult midbrain DA neurons. The knockout mice develop severe and progressive DA neuron-specific mitochondrial dysfunction resulting in neurodegeneration and parkinsonism. To gain further insights into pathophysiological events, we performed transcriptomic analyses of isolated DA neurons and found that mitochondrial dysfunction triggers an early onset immune response, which precedes mitochondrial swelling, mtDNA depletion, respiratory chain deficiency and cell death. Our experiments show that the immune response is an early pathological event when mitochondrial dysfunction is induced in adult midbrain DA neurons and that neuronal death may be promoted non-cell autonomously by the cross-talk and activation of surrounding glial cells.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
PLoS Genetics
volume
17
issue
9
pages
19 pages
publisher
Public Library of Science (PLoS)
external identifiers
  • scopus:85118097032
  • pmid:34570766
ISSN
1553-7404
DOI
10.1371/journal.pgen.1009822
language
English
LU publication?
yes
id
6da7f8f9-a582-45e3-a35f-616aae333302
date added to LUP
2021-10-04 16:22:10
date last changed
2024-06-15 17:25:47
@article{6da7f8f9-a582-45e3-a35f-616aae333302,
  abstract     = {{<p>Dopamine (DA) neurons of the midbrain are at risk to become affected by mitochondrial damage over time and mitochondrial defects have been frequently reported in Parkinson's disease (PD) patients. However, the causal contribution of adult-onset mitochondrial dysfunction to PD remains uncertain. Here, we developed a mouse model lacking Mitofusin 2 (MFN2), a key regulator of mitochondrial network homeostasis, in adult midbrain DA neurons. The knockout mice develop severe and progressive DA neuron-specific mitochondrial dysfunction resulting in neurodegeneration and parkinsonism. To gain further insights into pathophysiological events, we performed transcriptomic analyses of isolated DA neurons and found that mitochondrial dysfunction triggers an early onset immune response, which precedes mitochondrial swelling, mtDNA depletion, respiratory chain deficiency and cell death. Our experiments show that the immune response is an early pathological event when mitochondrial dysfunction is induced in adult midbrain DA neurons and that neuronal death may be promoted non-cell autonomously by the cross-talk and activation of surrounding glial cells.</p>}},
  author       = {{Filograna, Roberta and Lee, Seungmin and Tiklova, Katarina and Mennuni, Mara and Jonsson, Viktor and Ringnér, Markus and Gillberg, Linda and Sopova, Elena and Shupliakov, Oleg and Koolmeister, Camilla and Olson, Lars and Perlmann, Thomas and Larsson, Nils-Göran}},
  issn         = {{1553-7404}},
  language     = {{eng}},
  month        = {{10}},
  number       = {{9}},
  pages        = {{1009822--1009822}},
  publisher    = {{Public Library of Science (PLoS)}},
  series       = {{PLoS Genetics}},
  title        = {{Mitochondrial dysfunction in adult midbrain dopamine neurons triggers an early immune response}},
  url          = {{http://dx.doi.org/10.1371/journal.pgen.1009822}},
  doi          = {{10.1371/journal.pgen.1009822}},
  volume       = {{17}},
  year         = {{2021}},
}