Aneuploidy-induced proteostasis disruption impairs mitochondrial functions and mediates aggregation of mitochondrial precursor proteins through SQSTM1/p62

Prince Saforo Amponsah (), Jan-Eric Bökenkamp, Olha Kurpa, Svenja Lenhard, Anna Myronova, Daniel Osmar Vega Velazquez, Celina Hirschelmann, Christian Behrends, Johannes M. Herrmann, Markus Räschle and Zuzana Storchová ()
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Prince Saforo Amponsah: Rheinland-Pfälzische Technische Universität (RPTU) Kaiserslautern-Landau
Jan-Eric Bökenkamp: Rheinland-Pfälzische Technische Universität (RPTU) Kaiserslautern-Landau
Olha Kurpa: Rheinland-Pfälzische Technische Universität (RPTU) Kaiserslautern-Landau
Svenja Lenhard: Rheinland-Pfälzische Technische Universität (RPTU) Kaiserslautern-Landau
Anna Myronova: Rheinland-Pfälzische Technische Universität (RPTU) Kaiserslautern-Landau
Daniel Osmar Vega Velazquez: Rheinland-Pfälzische Technische Universität (RPTU) Kaiserslautern-Landau
Celina Hirschelmann: Rheinland-Pfälzische Technische Universität (RPTU) Kaiserslautern-Landau
Christian Behrends: Ludwig-Maximilians-Universität München
Johannes M. Herrmann: Rheinland-Pfälzische Technische Universität (RPTU) Kaiserslautern-Landau
Markus Räschle: Rheinland-Pfälzische Technische Universität (RPTU) Kaiserslautern-Landau
Zuzana Storchová: Rheinland-Pfälzische Technische Universität (RPTU) Kaiserslautern-Landau

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract Aneuploidy, or aberrant chromosomal content, disrupts cellular proteostasis through altered expression of numerous proteins. Aneuploid cells accumulate SQSTM1/p62-positive cytosolic bodies, exhibit impaired protein folding, and show altered proteasomal and lysosomal activity. Here, we employ p62 proximity- and affinity-based proteomics to elucidate p62 interactors in aneuploid cells and observe an enrichment of mitochondrial proteins. Increased protein aggregation and colocalization of p62 with both novel interactors and mitochondrial proteins is further confirmed by microscopy. Compared to parental diploids, aneuploid cells suffer from mitochondrial defects, including perinuclearly-clustered mitochondrial networks, elevated reactive oxygen species levels, reduced mitochondrial DNA abundance, and impaired protein import, leading to cytosolic accumulation of mitochondrial precursor proteins. Overexpression of heat shock proteins in aneuploid cells mitigates protein aggregation and decreases the colocalization of p62 with the mitochondrial protein TOMM20. Thus, proteotoxic stress caused by chromosome gains results in the sequestration of mitochondrial precursor proteins into cytosolic p62-bodies, thereby compromising mitochondrial function.

Date: 2025
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DOI: 10.1038/s41467-025-60857-4

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