MTOR modulates methamphetamine-induced toxicity through cell clearing systems

Gloria Lazzeri, Francesca Biagioni, Federica Fulceri, Carla L. Busceti, Maria C. Scavuzzo, Chiara Ippolito, Alessandra Salvetti, Paola Lenzi, Francesco Fornai

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Methamphetamine (METH) is abused worldwide, and it represents a threat for public health. METH exposure induces a variety of detrimental effects. In fact, METH produces a number of oxidative species, which lead to lipid peroxidation, protein misfolding, and nuclear damage. Cell clearing pathways such as ubiquitin-proteasome (UP) and autophagy (ATG) are involved in METH-induced oxidative damage. Although these pathways were traditionally considered to operate as separate metabolic systems, recent studies demonstrate their interconnection at the functional and biochemical level. Very recently, the convergence between UP and ATG was evidenced within a single organelle named autophagoproteasome (APP), which is suppressed by mTOR activation. In the present research study, the occurrence of APP during METH toxicity was analyzed. In fact, coimmunoprecipitation indicates a binding between LC3 and P20S particles, which also recruit p62 and alpha-synuclein. The amount of METH-induced toxicity correlates with APP levels. Specific markers for ATG and UP, such as LC3 and P20S in the cytosol, and within METH-induced vacuoles, were measured at different doses and time intervals following METH administration either alone or combined with mTOR modulators. Western blotting, coimmunoprecipitation, light microscopy, confocal microscopy, plain transmission electron microscopy, and immunogold staining were used to document the effects of mTOR modulation on METH toxicity and the merging of UP with ATG markers within APPs. METH-induced cell death is prevented by mTOR inhibition, while it is worsened by mTOR activation, which correlates with the amount of autophagoproteasomes. The present data, which apply to METH toxicity, are also relevant to provide a novel insight into cell clearing pathways to counteract several kinds of oxidative damage.

Original languageEnglish
Article number6124745
JournalOxidative Medicine and Cellular Longevity
Volume2018
DOIs
Publication statusPublished - Oct 29 2018

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Methamphetamine
Toxicity
Autophagy
Proteasome Endopeptidase Complex
Ubiquitin
Chemical activation
alpha-Synuclein
Confocal microscopy
Public health
Cell death
Nuclear Proteins
Vacuoles
Transmission Electron Microscopy
Merging
Confocal Microscopy
Organelles
Cytosol
Modulators
Lipid Peroxidation
Optical microscopy

ASJC Scopus subject areas

  • Biochemistry
  • Ageing
  • Cell Biology

Cite this

MTOR modulates methamphetamine-induced toxicity through cell clearing systems. / Lazzeri, Gloria; Biagioni, Francesca; Fulceri, Federica; Busceti, Carla L.; Scavuzzo, Maria C.; Ippolito, Chiara; Salvetti, Alessandra; Lenzi, Paola; Fornai, Francesco.

In: Oxidative Medicine and Cellular Longevity, Vol. 2018, 6124745, 29.10.2018.

Research output: Contribution to journalArticle

Lazzeri, Gloria ; Biagioni, Francesca ; Fulceri, Federica ; Busceti, Carla L. ; Scavuzzo, Maria C. ; Ippolito, Chiara ; Salvetti, Alessandra ; Lenzi, Paola ; Fornai, Francesco. / MTOR modulates methamphetamine-induced toxicity through cell clearing systems. In: Oxidative Medicine and Cellular Longevity. 2018 ; Vol. 2018.
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