PINK1 and Parkin mutations cause recessive Parkinson's disease (PD). In Drosophila and SH-SY5Y cells, Parkin is recruited by PINK1 to damaged mitochondria, where it ubiquitinates Mitofusins and consequently promotes mitochondrial fission and mitophagy

A Almeida

A Grünewald

A Rakovic

A Tanaka

AC Poole

AH Schapira

AK Lutz

Aleksandar Rakovic

Anne Grünewald

C Klein

C Piccoli

C Vives-Bauza

Christine Klein

D Narendra

DF Suen

DP Narendra

DV Jeyaraju

E Moro

E Ziviani

G Twig

H Chen

H Deng

H Mortiboys

IE Clark

J Park

Jan Kottwitz

JC Greene

JJ Palacino

JW Langston

K Hedrich

Katja Lohmann

L Flinn

Mark Cookson

ME Gegg

MM Cohen

N Matsuda

Norbert Brüggemann

O Rothfuss

P Kaiser

Peter P. Pramstaller

PP Pramstaller

R Verma

S Kawajiri

T Kanki

T Koshiba

T Yao

Y Pesah

Y Yang

PLoS ONE

English

PubMed

PINK1 and Parkin mutations cause recessive Parkinson's disease (PD). In Drosophila and SH-SY5Y cells, Parkin is recruited by PINK1 to damaged mitochondria, where it ubiquitinates Mitofusins and consequently promotes mitochondrial fission and mitophagy.Here, we investigated the impact of mutations in endogenous PINK1 and Parkin on the ubiquitination of mitochondrial fusion and fission factors and the mitochondrial network structure. Treating control fibroblasts with mitochondrial membrane potential (Δψ) inhibitors or H(2)O(2) resulted in ubiquitination of Mfn1/2 but not of OPA1 or Fis1. Ubiquitination of Mitofusins through the PINK1/Parkin pathway was observed within 1 h of treatment. Upon combined inhibition of Δψ and the ubiquitin proteasome system (UPS), no ubiquitination of Mitofusins was detected. Regarding morphological changes, we observed a trend towards increased mitochondrial branching in PD patient cells upon mitochondrial stress.For the first time in PD patient-derived cells, we demonstrate that mutations in PINK1 and Parkin impair ubiquitination of Mitofusins. In the presence of UPS inhibitors, ubiquitinated Mitofusin is deubiquitinated by the UPS but not degraded, suggesting that the UPS is involved in Mitofusin degradation

Peter P Pramstaller

Directory of Open Access Journals

Mutations in PINK1 and Parkin impair ubiquitination of Mitofusins in human fibroblasts.

peer reviewedPINK1 and Parkin mutations cause recessive Parkinson's disease (PD). In Drosophila and SH-SY5Y cells, Parkin is recruited by PINK1 to damaged mitochondria, where it ubiquitinates Mitofusins and consequently promotes mitochondrial fission and mitophagy.Here, we investigated the impact of mutations in endogenous PINK1 and Parkin on the ubiquitination of mitochondrial fusion and fission factors and the mitochondrial network structure. Treating control fibroblasts with mitochondrial membrane potential (Deltapsi) inhibitors or H(2)O(2) resulted in ubiquitination of Mfn1/2 but not of OPA1 or Fis1. Ubiquitination of Mitofusins through the PINK1/Parkin pathway was observed within 1 h of treatment. Upon combined inhibition of Deltapsi and the ubiquitin proteasome system (UPS), no ubiquitination of Mitofusins was detected. Regarding morphological changes, we observed a trend towards increased mitochondrial branching in PD patient cells upon mitochondrial stress.For the first time in PD patient-derived cells, we demonstrate that mutations in PINK1 and Parkin impair ubiquitination of Mitofusins. In the presence of UPS inhibitors, ubiquitinated Mitofusin is deubiquitinated by the UPS but not degraded, suggesting that the UPS is involved in Mitofusin degradation

Rakovic, Aleksandar

GRÜNEWALD, Anne

Kottwitz, Jan

Bruggemann, Norbert

Pramstaller, Peter P.

Lohmann, Katja

KLEIN, Christine

Open Repository and Bibliography - Luxembourg

Crossref

Mutations in PINK1 and Parkin Impair Ubiquitination of Mitofusins in Human Fibroblasts

A cryptic protease couples deubiquitination and degradation by the proteasome.

Analysis of differential DNA damage in the mitochondrial genome employing a semi-long run real-time PCR approach.

are ubiquitinated in a PINK1/parkin-dependent manner upon induction of mitophagy. Hum Mol Genet.

Assaying degradation and deubiquitination of a ubiquitinated substrate by purified 26S proteasomes.

Biological effects of the PINK1 c.1366C.T mutation: implications in Parkinson disease pathogenesis.

Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis.

Clinical spectrum of homozygous and heterozygous PINK1 mutations in a large German family with Parkinson disease: role of a single hit?

Coexistence of mutations in PINK1 and mitochondrial DNA in early onset parkinsonism.

Complex I deficiency and dopaminergic neuronal cell loss in parkin-deficient zebrafish (Danio rerio).

Differential effects of PINK1 nonsense and missense mutations on mitochondrial function and morphology.

Drosophila parkin mutants have decreased mass and cell size and increased sensitivity to oxygen radical stress.

Drosophila parkin requires PINK1 for mitochondrial translocation and ubiquitinates mitofusin.

Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin.

Effect of endogenous mutant and wild-type PINK1 on Parkin in fibroblasts from Parkinson disease patients.

Global approaches to understanding ubiquitination.

Isolation and characterization of tightly coupled mitochondria from neurons and astrocytes in primary culture.

Lewy body Parkinson’s disease in a large pedigree with 77 Parkin mutation carriers.

Loss of parkin or PINK1 function increases DRP1-dependent mitochondrial fragmentation.

Mitochondrial complex I deficiency in Parkinson’s disease.

Mitochondrial dynamics–fusion, fission, movement, and mitophagy–in neurodegenerative diseases.

Mitochondrial dysfunction and oxidative damage in parkin-deficient mice.

Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin.

Mitochondrial function and morphology are impaired in parkin-mutant fibroblasts.

Mitochondrial fusion, fission and autophagy as a quality control axis: the bioenergetic view.

Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants.

Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila Pink1 is rescued by Parkin.

Mitophagy in yeast occurs through a selective mechanism.

Parkin is recruited selectively to impaired mitochondria and promotes their autophagy.

Parkin overexpression selects against a deleterious mtDNA mutation in heteroplasmic cybrid cells.

Parkinson disease, 10 years after its genetic revolution: multiple clues to a complex disorder.

Phosphorylation and cleavage of presenilin-associated rhomboid-like protein (PARL) promotes changes in mitochondrial morphology.

PINK1 is recruited to mitochondria with parkin and associates with LC3 in mitophagy.

PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy.

PINK1-dependent recruitment of Parkin to mitochondria in mitophagy.

Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin.

Silencing of PINK1 expression affects mitochondrial DNA and oxidative phosphorylation in dopaminergic cells.

Structural basis of mitochondrial tethering by mitofusin complexes.

The mitochondrial fusion-promoting factor mitofusin is a substrate of the PINK1/parkin pathway.

The Parkinson’s disease genes pink1 and parkin promote mitochondrial fission and/or inhibit fusion in Drosophila.

The PINK1-Parkin pathway is involved in the regulation of mitochondrial remodeling process.

The PINK1/Parkin pathway regulates mitochondrial morphology.

Ubiquitin-proteasome-dependent degradation of a mitofusin, a critical regulator of mitochondrial fusion.

http://citeseerx.ist.psu.edu/viewdoc/summary?doi=10.1.1.293.9748

Mutations in PINK1 and Parkin Impair Ubiquitination of Mitofusins in Human Fibroblasts

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