Characterization of a natural variant of human NDP52 and its functional consequences on mitophagy.

Autor: Di Rita A; Department of Life Sciences, University of Siena, Siena, Italy.; Fondazione Toscana Life Sciences, Siena, Italy., Angelini DF; IRCCS Fondazione Santa Lucia, Rome, Italy., Maiorino T; Department of Molecular Medicine and Medical Biotechnology, University of Naples 'Federico II', Naples, Italy., Caputo V; Genomic Medicine Laboratory UILDM, IRCCS Santa Lucia Foundation, Rome, Italy.; Department of Biomedicine and Prevention, Tor Vergata University, Rome, Italy., Cascella R; Genomic Medicine Laboratory UILDM, IRCCS Santa Lucia Foundation, Rome, Italy.; Department of Biomedicine and Prevention, Tor Vergata University, Rome, Italy., Kumar M; Computational Biology Laboratory, Danish Cancer Society Research Center, Copenhagen, Denmark., Tiberti M; Computational Biology Laboratory, Danish Cancer Society Research Center, Copenhagen, Denmark., Lambrughi M; Computational Biology Laboratory, Danish Cancer Society Research Center, Copenhagen, Denmark., Wesch N; Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance, Goethe University Frankfurt, Frankfurt am Main, Germany., Löhr F; Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance, Goethe University Frankfurt, Frankfurt am Main, Germany., Dötsch V; Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance, Goethe University Frankfurt, Frankfurt am Main, Germany.; Structural Genomics Consortium, Buchmann Institute for Life Sciences, Goethe University Frankfurt, Frankfurt, Germany., Carinci M; Department of Medical Sciences, University of Ferrara, Ferrara, Italy., D'Acunzo P; Center for Dementia Research, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY, USA.; Department of Psychiatry, New York University School of Medicine, New York, NY, USA., Chiurchiù V; IRCCS Fondazione Santa Lucia, Rome, Italy.; Institute of Translational Pharmacology, National Council Research, Rome, Italy., Papaleo E; Computational Biology Laboratory, Danish Cancer Society Research Center, Copenhagen, Denmark.; Translational Disease Systems Biology, Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Protein Research University of Copenhagen, Copenhagen, Denmark., Rogov VV; Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance, Goethe University Frankfurt, Frankfurt am Main, Germany.; Structural Genomics Consortium, Buchmann Institute for Life Sciences, Goethe University Frankfurt, Frankfurt, Germany.; Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Frankfurt, Germany., Giardina E; Genomic Medicine Laboratory UILDM, IRCCS Santa Lucia Foundation, Rome, Italy.; Department of Biomedicine and Prevention, Tor Vergata University, Rome, Italy., Battistini L; IRCCS Fondazione Santa Lucia, Rome, Italy., Strappazzon F; IRCCS Fondazione Santa Lucia, Rome, Italy. f.strappazzon@hsantalucia.it.
Jazyk: angličtina
Zdroj: Cell death and differentiation [Cell Death Differ] 2021 Aug; Vol. 28 (8), pp. 2499-2516. Date of Electronic Publication: 2021 Mar 15.
DOI: 10.1038/s41418-021-00766-3
Abstrakt: The role of mitophagy, a process that allows the removal of damaged mitochondria from cells, remains unknown in multiple sclerosis (MS), a disease that is found associated with dysfunctional mitochondria. Here we have qualitatively and quantitatively studied the main players in PINK1-mediated mitophagy in peripheral blood mononuclear cells (PBMCs) of patients with relapsing-remitting MS. We found the variant c.491G>A (rs550510, p.G140E) of NDP52, one of the major mitophagy receptor genes, associated with a MS cohort. Through the characterization of this variant, we discovered that the residue 140 of human NDP52 is a crucial modulator of NDP52/LC3C binding, promoting the formation of autophagosomes in order to drive efficient mitophagy. In addition, we found that in the PBMC population, NDP52 is mainly expressed in B cells and by ensuring efficient mitophagy, it is able to limit the production of the proinflammatory cytokine TNF-α following cell stimulation. In sum, our results contribute to a better understanding of the role of NDP52 in mitophagy and underline, for the first time, a possible role of NDP52 in MS.
(© 2021. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.)
Databáze: MEDLINE
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