Dear All,

On Thursday (02.10) we will host dr. Karolina Szczepanowska (Laboratory of Metabolic Quality Control, The International Institute of Molecular Mechanisms and Machines, Polish Academy of Sciences). Her lecture will be entitled: "Proteolytic regulation of mitochondrial complexes in cancer and beyond ". The lecture will take place at 3 p.m. in the CN lecture hall and it will be followed by a get together.

Abstract

Mitochondrial function is largely defined by multimeric protein complexes that stay under the control of dedicated proteases, including ClpXP and LonP. The critical role of this machinery gains recognition in cancer research but remains poorly explored. We demonstrate that CLPP and LONP1 specifically contribute to the maintenance of protein complexes and comprehensively regulate substrates belonging to their matrix-exposed parts. While LONP1 governs proteolysis of numerous complex components and targets their aggregation-prone forms, CLPP degrades a small subset of folded and subassembled subunits. Paradoxically, genes encoding CLPP and LONP1 undergo recurrent simultaneous copy number losses in a subset of human cancers. Such deletions limit gene dosage for proteases, mediate their co-downregulation, and decrease the degradation of defined substrates. Cancers thrive even under protease shortage but become sensitive to stressors of complex homeostasis. We show that LONP1, rather than CLPP, plays a role in mitigating the consequences of cancer-related genomic alterations. Aneuploidy triggers changes in subunit stability under protease deficit and demands specific proteolytic assistance by LONP1. Our findings underscore the functional specialization of mitochondrial matrix proteases under cancer-associated stress.