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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

A new target for an old DUB: UCH-L1 regulates mitofusin-2 levels, altering mitochondrial morphology, function and calcium uptake

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Author(s):
Cerqueira, Fernanda M. [1, 2, 3] ; von Stockum, Sophia [3] ; Giacomello, Marta [4, 3] ; Goliand, Inna [2] ; Kakimoto, Pamela [5] ; Marchesan, Elena [3] ; De Stefani, Diego [4] ; Kowaltowski, Alicia J. [5] ; Ziviani, Elena [3] ; Shirihai, Orian S. [1, 6]
Total Authors: 10
Affiliation:
[1] Boston Univ, Obes Res Ctr, Mol Med, Sch Med, Boston, MA 02111 - USA
[2] Ben Gurion Univ Negev, Natl Inst Biotechnol Negev, IL-8410501 Beer Sheva - Israel
[3] Univ Padua, Dept Biol, I-35121 Padua - Italy
[4] Univ Padua, Dept Biomed Sci, I-35121 Padua - Italy
[5] Univ Sao Paulo, Inst Quim, Dept Bioquim, BR-05508900 Sao Paulo - Brazil
[6] Univ Calif Los Angeles, David Geffen Sch Med, UCLA Sect Endocrinol, Dept Med, Los Angeles, CA 90095 - USA
Total Affiliations: 6
Document type: Journal article
Source: REDOX BIOLOGY; v. 37, OCT 2020.
Web of Science Citations: 0
Abstract

UCH-L1 is a deubiquitinating enzyme (DUB), highly abundant in neurons, with a sub-cellular localization dependent on its farnesylation state. Despite UCH-L1's association with familial Parkinson's Disease (PD), the effects on mitochondrial bioenergetics and quality control remain unexplored. Here we investigated the role of UCH-L1 in mitochondrial dynamics and bioenergetics. We demonstrate that knock-down (KD) of UCH-L1 in different cell lines reduces the levels of the mitochondrial fusion protein Mitofusin-2, but not Mitofusin-1, resulting in mitochondrial enlargement and disruption of the tubular network. This was associated with lower tethering between mitochondria and the endoplasmic reticulum, consequently altering mitochondrial calcium uptake. Respiratory function was also altered, as UCH-L1 KD cells displayed higher proton leak and maximum respiratory capacity. Conversely, overexpression of UCH-L1 increased Mfn2 levels, an effect dramatically enhanced by the mutation of the farnesylation site (C220S), which drives UCH-L1 binding to membranes. These data indicate that the soluble cytosolic form of UCH-L1 regulates Mitofusin-2 levels and mitochondrial function. These effects are biologically conserved, since knock-down of the corresponding UCH-L1 ortholog in D. melanogaster reduces levels of the mitofusin ortholog Marf and also increases mitochondrial respiratory capacity. We thus show that Mfn-2 levels are directly affected by UCH-L1, demonstrating that the mitochondrial roles of DUBs go beyond controlling mitophagy rates. (AU)

FAPESP's process: 13/07937-8 - Redoxome - Redox Processes in Biomedicine
Grantee:Ohara Augusto
Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
FAPESP's process: 15/25862-0 - Hepatic bioenergetics and redox signaling in obesity murine model: integrative analysis of nutritional, hormonal, and inflammatory stimuli
Grantee:Pâmela Aiako Hypólito Brito Kakimoto
Support Opportunities: Scholarships in Brazil - Doctorate (Direct)