» Articles » PMID: 35740026

Bioenergetic and Autophagic Characterization of Skin Fibroblasts from Patients

Abstract

The objective of this study is to describe the alterations occurring during the neurodegenerative process in skin fibroblast cultures from patients. We characterized the oxidative stress, autophagy flux, small ubiquitin-related protein SUMO2/3 levels as well as the mitochondrial function in skin fibroblast cultures from patients. All metabolic and bioenergetic findings were further correlated with gene expression data obtained from RNA sequencing analysis. Fibroblasts from patients showed a 30% reduced expression of C9orf72, ~3-fold increased levels of oxidative stress and impaired mitochondrial function obtained by measuring the enzymatic activities of mitochondrial respiratory chain complexes, specifically of complex III activity. Furthermore, the results also reveal that patients showed an accumulation of p62 protein levels, suggesting the alteration of the autophagy process, and significantly higher protein levels of SUMO2/3 ( = 0.03). Our results provide new data reinforcing that cells suffer from elevated oxidative damage to biomolecules and organelles and from increased protein loads, leading to insufficient autophagy and an increase in SUMOylation processes.

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References
1.
Sellier C, Campanari M, Julie Corbier C, Gaucherot A, Kolb-Cheynel I, Oulad-Abdelghani M . Loss of C9ORF72 impairs autophagy and synergizes with polyQ Ataxin-2 to induce motor neuron dysfunction and cell death. EMBO J. 2016; 35(12):1276-97. PMC: 4910533. DOI: 10.15252/embj.201593350. View

2.
Gareau J, Lima C . The SUMO pathway: emerging mechanisms that shape specificity, conjugation and recognition. Nat Rev Mol Cell Biol. 2010; 11(12):861-71. PMC: 3079294. DOI: 10.1038/nrm3011. View

3.
Marmor-Kollet H, Siany A, Kedersha N, Knafo N, Rivkin N, Danino Y . Spatiotemporal Proteomic Analysis of Stress Granule Disassembly Using APEX Reveals Regulation by SUMOylation and Links to ALS Pathogenesis. Mol Cell. 2020; 80(5):876-891.e6. PMC: 7816607. DOI: 10.1016/j.molcel.2020.10.032. View

4.
Webster C, Smith E, Bauer C, Moller A, Hautbergue G, Ferraiuolo L . The C9orf72 protein interacts with Rab1a and the ULK1 complex to regulate initiation of autophagy. EMBO J. 2016; 35(15):1656-76. PMC: 4969571. DOI: 10.15252/embj.201694401. View

5.
Barth S, Glick D, Macleod K . Autophagy: assays and artifacts. J Pathol. 2010; 221(2):117-24. PMC: 2989884. DOI: 10.1002/path.2694. View