Molecular mechanisms of mitochondrial AAA+ proteases

Mitochondrial AAA+ proteases, LONP1, ClpXP, YME1L (i-AAA), and the m-AAA complex, maintain protein quality and shape organelle function. Growing interest in these enzymes stems from their association with neurodegeneration, cardiomyopathy, metabolic disease, and cancer. Recent structural and biophysical work clarifies how ATP-driven conformational cycles enable substrate recognition, unfolding, translocation, and proteolysis, and how assembly state, subunit composition, and regulatory inputs tune activity. These insights help interpret patient variants and guide experiments that connect mechanism to phenotype. Here we review shared mechanistic principles across the four proteases, contrast their architectures and regulatory features, and relate these properties to substrate selection and disease mechanisms, with emphasis on evidence from structural, biochemical, and cellular studies. We also survey strategies to modulate function. Small molecules, exemplified by Dordaviprone (ONC201), which activate human ClpP, provide proof of concept, and emerging modalities such as engineered macromolecules may offer the selectivity and localization required to correct disease mechanisms or exploit disease dependencies. By integrating mechanisms, disease links, and modulation strategies, this review provides a framework for translating basic insight on mitochondrial AAA+ proteases into new tools and, ultimately, therapies.