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

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.