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D'Angelo, D.* ; Sánchez-Vázquez, V.H.* ; Cartes-Saavedra, B.* ; Vecellio Reane, D. ; Cupo, R.R.* ; Delgado De La Herran, H.C. ; Ghirardo, G.* ; Shorter, J.* ; Wevers, R.A.* ; Wortmann, S.B.* ; Perocchi, F. ; Rizzuto, R.* ; Raffaello, A.* ; Hajnóczky, G.*

Dependence of mitochondrial calcium signalling and dynamics on the disaggregase, CLPB.

Nat. Commun. 16:2810 (2025)
DOI PMC
Cells utilize protein disaggregases to avoid abnormal protein aggregation that causes many diseases. Among these, caseinolytic peptidase B protein homolog (CLPB) is localized in the mitochondrial intermembrane space and linked to human disease. Upon CLPB loss, MICU1 and MICU2, regulators of the mitochondrial calcium uniporter complex (mtCU), and OPA1, a main mediator of mitochondrial fusion, become insoluble but the functional outcome remains unclear. In this work we demonstrate that CLPB is required to maintain mitochondrial calcium signalling and fusion dynamics. CLPB loss results in altered mtCU composition, interfering with mitochondrial calcium uptake independently of cytosolic calcium and mitochondrial membrane potential. Additionally, OPA1 decreases, and aggregation occurs, accompanied by mitochondrial fragmentation. Disease-associated mutations in the CLPB gene present in skin fibroblasts from patients also display mitochondrial calcium and structural changes. Thus, mtCU and fusion activity are dependent on CLPB, and their impairments might contribute to the disease caused by CLPB variants.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Fusion; Uniporter; Micu1; Neutropenia; Release
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Zeitschrift Nature Communications
Quellenangaben Band: 16, Heft: 1, Seiten: , Artikelnummer: 2810 Supplement: ,
Verlag Nature Publishing Group
Verlagsort London
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Diabetes and Obesity (IDO)
Förderungen European Union
Italian Ministry of University and Research
CARIPARO foundation
National Center for Gene Therapy and Drugs Based on RNA Technology - European Union - Next Generation EU
NIH
Italian Ministry of Health