Work

Loss of Drosophila ribosomal protein S6 kinase II causes mitochondrial dysfunction and cell death

Year: 2025

Type: article

Abstract: Mitochondria are dynamic organelles that are critical for energy production in high-demand tissues, such as the brain and muscle, with fusion and fission maintaining network integrity. The dysregulation of these processes underlies pathologies, such as neurodegenerative diseases. Ribosomal S6 kinases (RSK1-4) are effectors of extracellular signal-regulated kinases (ERKs), with roles in cell survival and metabolism. Here, we show that RSKs are essential for mitochondrial health. In human cells, siRNAs targeting any RSK isoform (RSK1-4) induced mitochondrial fragmentation and reduced viability. In Drosophila melanogaster, CRISPR-mediated loss of S6kII (the sole RSK orthologue) caused mitochondrial dysfunction and tissue degeneration in high-energy-demand organs, including the indirect flight muscle and brain, accompanied by autophagic activation. Notably, we rescued these defects by expressing human RSK4, underscoring functional conservation. Our findings establish RSKs as critical regulators of mitochondrial integrity, linking ERK signalling to organelle dynamics. This work identifies RSKs as regulators of mitochondrial health in energy-demanding tissues, providing insights into the mechanisms underlying neurodegeneration and strategies to target ERK/RSK-driven mitochondrial dysfunction.

Source: Disease Models & Mechanisms

DOI: 10.1242/dmm.052374

Authors: Ting Deng, Lajos Kalmar, Samantha Loh, Olivier E. Pardo, L. Miguel Martins

Institutions: University of Cambridge, MRC Toxicology Unit, Hammersmith Hospital, Imperial College London

Language: English

Topic: Mitochondrial Function and Pathology

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,750