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

Donato D’Angelo, Víctor H. Sánchez-Vázquez, Benjamín Cartes-Saavedra, Denis Vecellio Reane, Ryan R. Cupo, Hilda Delgado de la Herran, Giorgia Ghirardo, James Shorter, Ron A. Wevers, Saskia B. Wortmann, Fabiana Perocchi, Rosario Rizzuto (), Anna Raffaello () and György Hajnóczky ()
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Donato D’Angelo: University of Padua
Víctor H. Sánchez-Vázquez: Thomas Jefferson University
Benjamín Cartes-Saavedra: Thomas Jefferson University
Denis Vecellio Reane: Helmholtz Zentrum Munich
Ryan R. Cupo: Perelman School of Medicine at the University of Pennsylvania
Hilda Delgado de la Herran: Helmholtz Zentrum Munich
Giorgia Ghirardo: University of Padua
James Shorter: Perelman School of Medicine at the University of Pennsylvania
Ron A. Wevers: Radboud University Medical Centre
Saskia B. Wortmann: Salzburger Landesklinken (SALK) and Paracelsus Medical University
Fabiana Perocchi: Helmholtz Zentrum Munich
Rosario Rizzuto: University of Padua
Anna Raffaello: University of Padua
György Hajnóczky: Thomas Jefferson University

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-57641-9

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