22 | TRANSCRIPTIONAL AND POST-TRANSLATIONAL NETWORKS COORDINATE SELECTIVE AUTOPHAGY TO MAINTAIN ORGANELLE HOMEOSTASIS

K. Hartfelt¹, M. Petraroia², T. Persichini², M. Colasanti², C. Di Malta³, F. Cecconi⁴, V. Cianfanelli² | ¹Unit of Cell Stress and Survival, Danish Cancer Institute, Copenhagen, Denmark; ²Dept. of Science, University Roma TRE, Rome, Italy; ³Telethon Institute of Genetics and Medicine, Naples, Italy; ⁴Dept. of Basic Biotechnological Sciences, Intensive Care and Perioperative Clinics Research, Catholic University of the Sacred Heart, Rome, Italy

Organelle homeostasis depends on a tight balance between biogenesis and selective autophagy-mediated degradation. Dysregulation of this balance underlies neurodegenerative diseases, cancer, and resistance to chemotherapy. Our research aims to dissect the molecular mechanisms that coordinate selective autophagy with organelle biogenesis, with a focus on identifying new regulatory axes and potential therapeutic targets.
We previously identified PP2A-B55α/PPP2R2A as a master regulator of mitochondrial homeostasis. Upon mitochondrial damage, PP2A-B55α orchestrates both mitophagy induction and execution while simultaneously controlling mitochondrial biogenesis. Importantly, PP2A-B55α targeting rescued neurodegenerative phenotypes in a fly model of Parkinson's disease1.
Extending this framework to other organelles, we are now investigating the regulation of pexophagy, a selective autophagy pathway targeting peroxisomes whose dysfunction causes severe metabolic diseases. We identify a novel regulatory axis that couples a specific stress signal to key transcriptional regulators of autophagy, promoting efficient peroxisome degradation. Notably, components of this axis are altered in a subtype of kidney cancer, pointing to a previously unrecognized link between pexophagy dysregulation and oncogenesis.
Altogether, these results indicate that common regulatory nodes - including kinase-phosphatase networks and transcriptional programs - coordinate selective autophagy across distinct organelles, suggesting that targeting these convergent mechanisms may offer broad therapeutic opportunities.
Acknowledgments: This work was supported by the MUR (project ID: P2022TJZYZ; title: “Post-translational and transcriptional regulation of peroxisome turnover in health and disease,” funded by the European Union - Next Generation EU, Piano Nazionale di Ripresa e Resilienza, Mission 4, Component 2, Investment 1.1, Progetti di Ricerca di Rilevante Interesse Nazionale PRIN 2022 – MUR, CUP F53D23008670001; MUR-Italy Departments of Excellence 2023-2027 to the Dept. of Science, Univ. Roma Tre).