Aneuploidy-Induced Proteome Imbalance Disrupts Mitochondrial Function

A recent study conducted by researchers at the Rheinland-Pfälzische Technische Universitӓt Kaiserslautern-Landau (RPTU) has unveiled significant insights into how aneuploidy, a condition characterized by abnormal chromosome numbers, affects cellular functions, particularly mitochondrial activity. Published in the journal Nature Communications on June 27, 2025, the research highlights the link between proteome imbalance and mitochondrial dysfunction, which could have profound implications for cancer therapy.

Aneuploidy is prevalent in various cancers and genetic disorders, including Down syndrome. Healthy human cells typically contain 23 pairs of chromosomes; however, errors during cell division can result in daughter cells with either extra or missing chromosomes. This study, led by Professor Zuzana Storchová and Dr. Prince Saforo Amponsah, specifically examined colorectal cancer cell lines modified to possess additional chromosomes, revealing that these cells accumulate harmful protein aggregates.

"Cells with extra chromosomes exhibited significantly higher concentrations of sequestosome 1 (SQSTM1), a protein involved in recycling damaged cellular components," stated Dr. Amponsah. The aggregation of SQSTM1 was found to sequester mitochondrial precursor proteins, hindering their transport into mitochondria and thus impairing mitochondrial function.

This proteomic disruption raises critical concerns regarding the metabolic adaptations of cancer cells, as they often face proteotoxic stress due to chromosomal abnormalities. "Our findings suggest that cancer cells may modify their mitochondrial metabolism as a survival strategy, potentially contributing to drug resistance in aneuploid tumors," Dr. Amponsah added.

Experts in the field have expressed varying perspectives on the implications of these findings. Dr. Emily Carter, a molecular biologist at Stanford University, noted, "This research provides a novel framework for understanding the metabolic flexibility of cancer cells. It emphasizes the need for therapeutic strategies that target mitochondrial function in aneuploid cancers."

However, not all scientists are convinced that targeting mitochondrial pathways will yield significant benefits. Dr. Robert Lang, an oncologist at Johns Hopkins University, cautioned, "While the findings are intriguing, the complexity of cellular metabolism in cancer makes it challenging to develop effective interventions based solely on these mechanisms. Further research is essential."

The study also highlights the physiological relevance of the utilized cell lines, which mimic the genomic imbalances observed in various pathological conditions, including aging. The collaborative research project, part of the STRESSistance graduate school program funded by the German Research Foundation, aims to deepen the understanding of mitochondrial adaptation in relation to nuclear and mitochondrial genome discrepancies.

In conclusion, while the research underscores a previously unexplored connection between genomic abnormalities and mitochondrial dysfunction, future studies are necessary to explore the therapeutic potential of targeting these pathways in cancer treatment. As the field progresses, the hope is that these insights will lead to improved outcomes for patients suffering from aneuploid cancers.

For those interested in the detailed methodology and findings, the complete study can be accessed through the Nature Communications journal, reference: Amponsah, P. S., et al. (2025). Aneuploidy-induced proteostasis disruption impairs mitochondrial functions and mediates aggregation of mitochondrial precursor proteins through SQSTM1/p62.