Dataset Information

Degradation of altered mitochondria by autophagy is impaired in Lafora disease.

ABSTRACT: Lafora disease (LD) is a fatal neurodegenerative disorder caused mostly by mutations in either of two genes encoding laforin and malin. LD is characterized by accumulation of a poorly branched form of glycogen in the cytoplasm of neurons and other cells. We previously reported dysfunctional mitochondria in different LD models. Now, using mitochondrial uncouplers and respiratory chain inhibitors, we have investigated with human fibroblasts a possible alteration in the selective degradation of damaged mitochondria (mitophagy) in LD. By flow cytometry of MitoTracker-labelled cells and measuring the levels of various mitochondrial proteins by western blot, we found in LD fibroblasts a partial impairment in the increased mitochondrial degradation produced by these treatments. In addition, colocalization of mitochondrial and lysosomal markers decreased in LD fibroblasts. All these results are consistent with a partial impairment in the induced autophagic degradation of dysfunctional mitochondria in LD fibroblasts. However, canonical recruitment of Parkin to mitochondria under these conditions remained unaffected in LD fibroblasts, and also in SH-SY5Y cells after malin and laforin overexpression. Neither mitochondrial localization nor protein levels of Bcl-2-like protein 13, another component of the mitophagic machinery that operates under these conditions, were affected in LD fibroblasts. In contrast, although these treatments raised autophagy in both control and LD fibroblasts, this enhanced autophagy was clearly lower in the latter cells. Therefore, the autophagic degradation of altered mitochondria is impaired in LD, which is due to a partial defect in the autophagic response and not in the canonical mitophagy signalling pathways.

SUBMITTER: Lahuerta M

PROVIDER: S-EPMC5986609 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Degradation of altered mitochondria by autophagy is impaired in Lafora disease.

Lahuerta Marcos M Aguado Carmen C Sánchez-Martín Pablo P Sanz Pascual P Knecht Erwin E

The FEBS journal 20180423 11

Lafora disease (LD) is a fatal neurodegenerative disorder caused mostly by mutations in either of two genes encoding laforin and malin. LD is characterized by accumulation of a poorly branched form of glycogen in the cytoplasm of neurons and other cells. We previously reported dysfunctional mitochondria in different LD models. Now, using mitochondrial uncouplers and respiratory chain inhibitors, we have investigated with human fibroblasts a possible alteration in the selective degradation of dam ...[more]

PMID: 29645350

Similar Datasets

Project description:Two pathways are responsible for the majority of regulated protein catabolism in eukaryotic cells: the ubiquitin-proteasome system (UPS) and lysosomal self-degradation through autophagy. Both processes are necessary for cellular homeostasis by ensuring continuous turnover and quality control of most intracellular proteins. Recent studies established that both UPS and autophagy are capable of selectively eliminating ubiquitinated proteins and that autophagy may partially compensate for the lack of proteasomal degradation, but the molecular links between these pathways are poorly characterized.Here we show that autophagy is enhanced by the silencing of genes encoding various proteasome subunits (?, ? or regulatory) in larval fat body cells. Proteasome inactivation induces canonical autophagy, as it depends on core autophagy genes Atg1, Vps34, Atg9, Atg4 and Atg12. Large-scale accumulation of aggregates containing p62 and ubiquitinated proteins is observed in proteasome RNAi cells. Importantly, overexpressed Atg8a reporters are captured into the cytoplasmic aggregates, but these do not represent autophagosomes. Loss of p62 does not block autophagy upregulation upon proteasome impairment, suggesting that compensatory autophagy is not simply due to the buildup of excess cargo. One of the best characterized substrates of UPS is the ? subunit of hypoxia-inducible transcription factor 1 (HIF-1?), which is continuously degraded by the proteasome during normoxic conditions. Hypoxia is a known trigger of autophagy in mammalian cells, and we show that genetic activation of hypoxia signaling also induces autophagy in Drosophila. Moreover, we find that proteasome inactivation-induced autophagy requires sima, the Drosophila ortholog of HIF-1?.We have characterized proteasome inactivation- and hypoxia signaling-induced autophagy in the commonly used larval Drosophila fat body model. Activation of both autophagy and hypoxia signaling was implicated in various cancers, and mutations affecting genes encoding UPS enzymes have recently been suggested to cause renal cancer. Our studies identify a novel genetic link that may play an important role in that context, as HIF-1?/sima may contribute to upregulation of autophagy by impaired proteasomal activity.

Dataset Information

Degradation of altered mitochondria by autophagy is impaired in Lafora disease.

Publications

Degradation of altered mitochondria by autophagy is impaired in Lafora disease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets