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Cited by 124Autophagy in Disease and TherapyDown syndrome and intellectual disability researchCalcium signaling and nucleotide metabolism

mTOR hyperactivation in Down Syndrome underlies deficits in autophagy induction, autophagosome formation, and mitophagy

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Bordi, Matteo, Darji, Sandipkumar, Sato, Yutaka, Mellén, Marian, Berg, Martin J., Kumar, Asok, Jiang, Ying, Nixon, Ralph A.·2019·Cell Death & Disease
DOI 10.1038/s41419-019-1752-5PMC PMC6646359
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Abstract

Down syndrome (DS), a complex genetic disorder caused by chromosome 21 trisomy, is associated with mitochondrial dysfunction leading to the accumulation of damaged mitochondria. Here we report that mitophagy, a form of selective autophagy activated to clear damaged mitochondria is deficient in primary human fibroblasts derived from individuals with DS leading to accumulation of damaged mitochondria with consequent increases in oxidative stress. We identified two molecular bases for this mitophagy deficiency: PINK1/PARKIN impairment and abnormal suppression of macroautophagy. First, strongly downregulated PARKIN and the mitophagic adaptor protein SQSTM1/p62 delays PINK1 activation to impair mitophagy induction after mitochondrial depolarization by CCCP or antimycin A plus oligomycin. Secondly, mTOR is strongly hyper-activated, which globally suppresses macroautophagy induction and the transcriptional expression of proteins critical for autophagosome formation such as ATG7, ATG3 and FOXO1. Notably, inhibition of mTOR complex 1 (mTORC1) and complex 2 (mTORC2) using AZD8055 (AZD) restores autophagy flux, PARKIN/PINK initiation of mitophagy, and the clearance of damaged mitochondria by mitophagy. These results recommend mTORC1-mTORC2 inhibition as a promising candidate therapeutic strategy for Down Syndrome.

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Crossref · 10.1038/s41419-019-1752-5

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  • In DS fibroblasts, only MAP1LC3B was upregulated among induction-list genes; 17 targets did not change, and ATG7 and GABARAPL1 were highly downregulated.

    “Only DS fibroblasts showed the upregulation of MAP1LC3B, but, on the contrary, 17 targets did not change, and ATG7 and GABARAPL1 were highly downregulated, as previously indicated [27].”

    From A gene toolbox for monitoring autophagy transcription (2021) · cites this paper as [27]

    The Results section on macroautophagy in DS fibroblasts (page unavailable) reports increased MAP1LC3B mRNA and marked downregulation of ATG7 at both protein and mRNA levels. Our copy does not substantiate that MAP1LC3B was the only upregulated gene, that 17 targets were unchanged, or that GABARAPL1 was downregulated. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • The authors identified 20 targets related to autophagy activation and validated them by qPCR: ATG10, ATG14, ATG16L1, ATG3, ATG4, ATG7, ATG9A, BCL2, GABARAP, GABARAPL1, MAP1LC3B, NBR1, OPTN, PINK1, SQSTM1, ULK1, ULK2, UVRAG, WDR45, WIPI1.

    “In a first case, starting from experimental data available in the literature, we identified 20 targets related to autophagy activation and validated them by qPCR: ATG10, ATG14, ATG16L1, ATG3, ATG4, ATG7, ATG9A, BCL2, GABARAP, GABARAPL1, MAP1LC3B, NBR1, OPTN, PINK1, SQSTM1, ULK1, ULK2, UVRAG, WDR45, WIPI1 (Fig. 2) [18–27].”

    From A gene toolbox for monitoring autophagy transcription (2021) · cites this paper as [27]

    The Results section on macroautophagy in Down syndrome fibroblasts links several listed genes, including ATG3, ATG7, MAP1LC3B and SQSTM1, to autophagosome formation or autophagy changes. The paper does not establish the entire 20-gene list as targets related to autophagy activation. The citing authors describe the selection and qPCR validation as their own work, not as work performed by this source. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Down syndrome primary fibroblasts have mTORC1 hyperactivation associated with inhibition of autophagy induction.

    “in which it has been reported an mTORC1 hyperactivation associated to inhibition of autophagy induction [27]”

    From A gene toolbox for monitoring autophagy transcription (2021) · cites this paper as [27]

  • The autophagy core list was used for gene set enrichment analysis on published RNA-seq datasets from starved cells or Down syndrome primary fibroblasts.

    “Further, we used the “autophagy core” list for gene set enrichment analysis by means of the published RNA-sequencing (RNA-seq) dataset, performed on starved cells [31] or on Down syndrome primary fibroblasts, in which it has been reported an mTORC1 hyperactivation associated to inhibition of autophagy induction [27], and thus demonstrating its effective applicability.”

    From A gene toolbox for monitoring autophagy transcription (2021) · cites this paper as [27]

  • The restricted "induction list" for the prediction of autophagy activation state is made of 20 targets and was obtained by combining data from previous publications documenting increased mRNA expression following autophagy induction.

    “The restricted “induction list” for the prediction of autophagy activation state, made by 20 targets, was obtained combining data from previous publications [18–27], in which have been documented the increase of the mRNA expression following autophagy induction.”

    From A gene toolbox for monitoring autophagy transcription (2021) · cites this paper as [27]

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Cited by

Sorted by citations

Authors
Bordi, M., Darji, S., Sato, Y., Mellén, M., Berg, M. J., Kumar, A., Jiang, Y., & Nixon, R. A.
Affiliations
  • University of Rome Tor Vergata (IT)
  • Nathan Kline Institute for Psychiatric Research (US)
  • Universidad Francisco de Vitoria (ES)
Corresponding author
Bordi, Matteo
ORCID
Venue
Cell Death & Disease
Publisher
Springer Science and Business Media LLC
Published
2019-07-22
Volume
10
Issue
8
Pages
563-563
ISSN
2041-4889 (ISSN-L)
DOI
10.1038/s41419-019-1752-5
PMC
PMC6646359
OpenAlex
W2963387403
Cited by
124
References
15
Citations by year
2026: 16 · 2025: 15 · 2024: 19 · 2023: 11 · 2022: 18 · 2021: 28 · 2020: 16 · 2019: 1
FWCI
11.99
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Death and Disease (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Deposito Digital UFV (Francisco de Vitoria University) (submittedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • PubliCatt (Università Cattolica del Sacro Cuore) (submittedVersion, other-oa)
Funders
U.S. Department of Health & Human Services | NIH | National Institute on Aging (P01 AG017617)
Topics
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
Keywords
Down syndrome, mTOR hyperactivation, mitophagy, autophagy, PINK1, Parkin, p62, mitochondrial dysfunction, oxidative stress, mTORC1, mTORC2, AZD8055, autophagosome formation, fibroblasts, therapeutic target
MeSH terms
Autophagosomes, Mechanistic Target of Rapamycin Complex 1, Mechanistic Target of Rapamycin Complex 2, PTEN-Induced Putative Kinase, Cells, Cultured, Child, Preschool, Down Syndrome, Fibroblasts, Humans, Infant, Lysosomes, Mitochondria, Morpholines, Protein Kinases, Skin, Signal Transduction, Ubiquitin-Protein Ligases, TOR Serine-Threonine Kinases, Mitophagy

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