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PARKIN is not required to sustain OXPHOS function in adult mammalian tissues

Filograna, Roberta ; Gerlach, Jule ; Choi, Hae-Na ; Rigoni, Giovanni ; Barbaro, Michela ; Oscarson, Mikael ; Lee, Seungmin ; Tiklova, Katarina ; Ringnér, Markus LU orcid and Koolmeister, Camilla , et al. (2024) In npj Parkinson's Disease 10.
Abstract

Loss-of-function variants in the PRKN gene encoding the ubiquitin E3 ligase PARKIN cause autosomal recessive early-onset Parkinson's disease (PD). Extensive in vitro and in vivo studies have reported that PARKIN is involved in multiple pathways of mitochondrial quality control, including mitochondrial degradation and biogenesis. However, these findings are surrounded by substantial controversy due to conflicting experimental data. In addition, the existing PARKIN-deficient mouse models have failed to faithfully recapitulate PD phenotypes. Therefore, we have investigated the mitochondrial role of PARKIN during ageing and in response to stress by employing a series of conditional Parkin knockout mice. We report that PARKIN loss does not... (More)

Loss-of-function variants in the PRKN gene encoding the ubiquitin E3 ligase PARKIN cause autosomal recessive early-onset Parkinson's disease (PD). Extensive in vitro and in vivo studies have reported that PARKIN is involved in multiple pathways of mitochondrial quality control, including mitochondrial degradation and biogenesis. However, these findings are surrounded by substantial controversy due to conflicting experimental data. In addition, the existing PARKIN-deficient mouse models have failed to faithfully recapitulate PD phenotypes. Therefore, we have investigated the mitochondrial role of PARKIN during ageing and in response to stress by employing a series of conditional Parkin knockout mice. We report that PARKIN loss does not affect oxidative phosphorylation (OXPHOS) capacity and mitochondrial DNA (mtDNA) levels in the brain, heart, and skeletal muscle of aged mice. We also demonstrate that PARKIN deficiency does not exacerbate the brain defects and the pro-inflammatory phenotype observed in mice carrying high levels of mtDNA mutations. To rule out compensatory mechanisms activated during embryonic development of Parkin-deficient mice, we generated a mouse model where loss of PARKIN was induced in adult dopaminergic (DA) neurons. Surprisingly, also these mice did not show motor impairment or neurodegeneration, and no major transcriptional changes were found in isolated midbrain DA neurons. Finally, we report a patient with compound heterozygous PRKN pathogenic variants that lacks PARKIN and has developed PD. The PARKIN deficiency did not impair OXPHOS activities or induce mitochondrial pathology in skeletal muscle from the patient. Altogether, our results argue that PARKIN is dispensable for OXPHOS function in adult mammalian tissues.

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publication status
published
subject
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npj Parkinson's Disease
volume
10
article number
93
publisher
Springer Nature
external identifiers
  • pmid:38684669
  • scopus:85191796898
ISSN
2373-8057
DOI
10.1038/s41531-024-00707-0
language
English
LU publication?
yes
id
ee38432e-c832-460c-98d7-3e74e2934eb5
date added to LUP
2024-05-02 11:42:32
date last changed
2024-06-04 15:07:46
@article{ee38432e-c832-460c-98d7-3e74e2934eb5,
  abstract     = {{<p>Loss-of-function variants in the PRKN gene encoding the ubiquitin E3 ligase PARKIN cause autosomal recessive early-onset Parkinson's disease (PD). Extensive in vitro and in vivo studies have reported that PARKIN is involved in multiple pathways of mitochondrial quality control, including mitochondrial degradation and biogenesis. However, these findings are surrounded by substantial controversy due to conflicting experimental data. In addition, the existing PARKIN-deficient mouse models have failed to faithfully recapitulate PD phenotypes. Therefore, we have investigated the mitochondrial role of PARKIN during ageing and in response to stress by employing a series of conditional Parkin knockout mice. We report that PARKIN loss does not affect oxidative phosphorylation (OXPHOS) capacity and mitochondrial DNA (mtDNA) levels in the brain, heart, and skeletal muscle of aged mice. We also demonstrate that PARKIN deficiency does not exacerbate the brain defects and the pro-inflammatory phenotype observed in mice carrying high levels of mtDNA mutations. To rule out compensatory mechanisms activated during embryonic development of Parkin-deficient mice, we generated a mouse model where loss of PARKIN was induced in adult dopaminergic (DA) neurons. Surprisingly, also these mice did not show motor impairment or neurodegeneration, and no major transcriptional changes were found in isolated midbrain DA neurons. Finally, we report a patient with compound heterozygous PRKN pathogenic variants that lacks PARKIN and has developed PD. The PARKIN deficiency did not impair OXPHOS activities or induce mitochondrial pathology in skeletal muscle from the patient. Altogether, our results argue that PARKIN is dispensable for OXPHOS function in adult mammalian tissues.</p>}},
  author       = {{Filograna, Roberta and Gerlach, Jule and Choi, Hae-Na and Rigoni, Giovanni and Barbaro, Michela and Oscarson, Mikael and Lee, Seungmin and Tiklova, Katarina and Ringnér, Markus and Koolmeister, Camilla and Wibom, Rolf and Riggare, Sara and Nennesmo, Inger and Perlmann, Thomas and Wredenberg, Anna and Wedell, Anna and Motori, Elisa and Svenningsson, Per and Larsson, Nils-Göran}},
  issn         = {{2373-8057}},
  language     = {{eng}},
  month        = {{04}},
  publisher    = {{Springer Nature}},
  series       = {{npj Parkinson's Disease}},
  title        = {{PARKIN is not required to sustain OXPHOS function in adult mammalian tissues}},
  url          = {{http://dx.doi.org/10.1038/s41531-024-00707-0}},
  doi          = {{10.1038/s41531-024-00707-0}},
  volume       = {{10}},
  year         = {{2024}},
}