Lysosomal dysfunction and overload of nucleosides in thymidine phosphorylase deficiency of MNGIE.
Humans
Lysosomes
/ metabolism
Thymidine Phosphorylase
/ metabolism
Mitochondrial Encephalomyopathies
/ metabolism
Fibroblasts
/ metabolism
DNA, Mitochondrial
/ genetics
Mitochondria
/ metabolism
Nucleosides
/ metabolism
Intestinal Pseudo-Obstruction
/ metabolism
Ophthalmoplegia
/ metabolism
Muscular Dystrophy, Oculopharyngeal
/ metabolism
Male
Female
Skin
/ pathology
Lysosomal-Associated Membrane Protein 2
/ metabolism
Lysosomal dysfunction
MNGIE
Nucleotide metabolism
TYMP
Thymidine phosphorylase
Journal
Journal of translational medicine
ISSN: 1479-5876
Titre abrégé: J Transl Med
Pays: England
ID NLM: 101190741
Informations de publication
Date de publication:
13 May 2024
13 May 2024
Historique:
received:
20
02
2024
accepted:
06
05
2024
medline:
14
5
2024
pubmed:
14
5
2024
entrez:
13
5
2024
Statut:
epublish
Résumé
Inherited deficiency of thymidine phosphorylase (TP), encoded by TYMP, leads to a rare disease with multiple mitochondrial DNA (mtDNA) abnormalities, mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). However, the impact of TP deficiency on lysosomes remains unclear, which are important for mitochondrial quality control and nucleic acid metabolism. Muscle biopsy tissue and skin fibroblasts from MNGIE patients, patients with m.3243 A > G mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) and healthy controls (HC) were collected to perform mitochondrial and lysosomal functional analyses. In addition to mtDNA abnormalities, compared to controls distinctively reduced expression of LAMP1 and increased mitochondrial content were detected in the muscle tissue of MNGIE patients. Skin fibroblasts from MNGIE patients showed decreased expression of LAMP2, lowered lysosomal acidity, reduced enzyme activity and impaired protein degradation ability. TYMP knockout or TP inhibition in cells can also induce the similar lysosomal dysfunction. Using lysosome immunoprecipitation (Lyso- IP), increased mitochondrial proteins, decreased vesicular proteins and V-ATPase enzymes, and accumulation of various nucleosides were detected in lysosomes with TP deficiency. Treatment of cells with high concentrations of dThd and dUrd also triggers lysosomal dysfunction and disruption of mitochondrial homeostasis. Therefore, the results provided evidence that TP deficiency leads to nucleoside accumulation in lysosomes and lysosomal dysfunction, revealing the widespread disruption of organelles underlying MNGIE.
Identifiants
pubmed: 38741129
doi: 10.1186/s12967-024-05275-8
pii: 10.1186/s12967-024-05275-8
doi:
Substances chimiques
Thymidine Phosphorylase
EC 2.4.2.4
DNA, Mitochondrial
0
Nucleosides
0
Lysosomal-Associated Membrane Protein 2
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
449Subventions
Organisme : the National Key Research and Development Program of China
ID : 2021YFC2700904
Informations de copyright
© 2024. The Author(s).
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