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

Autor(es)

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]}

Afiliação do(s) autor(es)

^[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

• Tipo de documento: Artigo Científico
• Fonte: REDOX BIOLOGY; v. 37, OCT 2020.
• Citações Web of Science: 0

Resumo

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)

• Processo FAPESP: 13/07937-8 - Redoxoma
• Beneficiário: Ohara Augusto
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 15/25862-0 - Bioenergética e sinalização redox hepática em modelo murino de obesidade: análise integrativa de estímulos nutricionais, hormonais e inflamatórios
• Beneficiário: Pâmela Aiako Hypólito Brito Kakimoto
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto