PMID- 32956978
OWN - NLM
STAT- MEDLINE
DCOM- 20210524
LR  - 20210524
IS  - 2213-2317 (Electronic)
IS  - 2213-2317 (Linking)
VI  - 37
DP  - 2020 Oct
TI  - A new target for an old DUB: UCH-L1 regulates mitofusin-2 levels, altering 
      mitochondrial morphology, function and calcium uptake.
PG  - 101676
LID - S2213-2317(20)30881-8 [pii]
LID - 10.1016/j.redox.2020.101676 [doi]
LID - 101676
AB  - 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 UCHL-1 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.
CI  - Copyright (c) 2020. Published by Elsevier B.V.
FAU - Cerqueira, Fernanda M
AU  - Cerqueira FM
AD  - Obesity Research Center, Molecular Medicine, Boston University School of 
      Medicine, Boston, MA, 02111, USA; National Institute for Biotechnology in the 
      Negev, Ben Gurion University, Beer-Sheva, 8410501, Israel; Department of Biology, 
      University of Padua, Padua, 35121, Italy.
FAU - von Stockum, Sophia
AU  - von Stockum S
AD  - Department of Biology, University of Padua, Padua, 35121, Italy.
FAU - Giacomello, Marta
AU  - Giacomello M
AD  - Department of Biology, University of Padua, Padua, 35121, Italy; Department of 
      Biomedical Sciences, University of Padua, 35121, Italy.
FAU - Goliand, Inna
AU  - Goliand I
AD  - National Institute for Biotechnology in the Negev, Ben Gurion University, 
      Beer-Sheva, 8410501, Israel.
FAU - Kakimoto, Pamela
AU  - Kakimoto P
AD  - Departmento de Bioquimica, Instituto de Quimica, Universidade de Sao Paulo, Sao 
      Paulo, 05508-900, Brazil.
FAU - Marchesan, Elena
AU  - Marchesan E
AD  - Department of Biology, University of Padua, Padua, 35121, Italy.
FAU - De Stefani, Diego
AU  - De Stefani D
AD  - Department of Biomedical Sciences, University of Padua, 35121, Italy.
FAU - Kowaltowski, Alicia J
AU  - Kowaltowski AJ
AD  - Departmento de Bioquimica, Instituto de Quimica, Universidade de Sao Paulo, Sao 
      Paulo, 05508-900, Brazil.
FAU - Ziviani, Elena
AU  - Ziviani E
AD  - Department of Biology, University of Padua, Padua, 35121, Italy.
FAU - Shirihai, Orian S
AU  - Shirihai OS
AD  - Obesity Research Center, Molecular Medicine, Boston University School of 
      Medicine, Boston, MA, 02111, USA; UCLA Section of Endocrinology, Department of 
      Medicine, David Geffen School of Medicine, UCLA, CA, 9095-7073, USA. Electronic 
      address: OShirihai@mednet.ucla.edu.
LA  - eng
GR  - R01 DK099618/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20200807
PL  - Netherlands
TA  - Redox Biol
JT  - Redox biology
JID - 101605639
RN  - EC 3.4.19.12 (Ubiquitin Thiolesterase)
RN  - EC 3.6.1.- (GTP Phosphohydrolases)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Animals
MH  - Biological Transport
MH  - *Calcium/metabolism
MH  - *Drosophila melanogaster/genetics/metabolism
MH  - Endoplasmic Reticulum/metabolism
MH  - GTP Phosphohydrolases
MH  - *Mitochondria/genetics/metabolism
MH  - *Ubiquitin Thiolesterase/metabolism
PMC - PMC7509235
OTO - NOTNLM
OT  - Deubiquitinase
OT  - Mitochondria
OT  - Mitochondrial function
OT  - Parkinson's disease
COIS- The authors declare no conflict of interest.
EDAT- 2020/09/22 06:00
MHDA- 2021/05/25 06:00
PMCR- 2020/08/07
CRDT- 2020/09/21 20:16
PHST- 2020/05/18 00:00 [received]
PHST- 2020/07/13 00:00 [revised]
PHST- 2020/08/03 00:00 [accepted]
PHST- 2020/09/22 06:00 [pubmed]
PHST- 2021/05/25 06:00 [medline]
PHST- 2020/09/21 20:16 [entrez]
PHST- 2020/08/07 00:00 [pmc-release]
AID - S2213-2317(20)30881-8 [pii]
AID - 101676 [pii]
AID - 10.1016/j.redox.2020.101676 [doi]
PST - ppublish
SO  - Redox Biol. 2020 Oct;37:101676. doi: 10.1016/j.redox.2020.101676. Epub 2020 Aug 
      7.