Elena Ziviani 11th International Symposium on Autophagy 2025

Elena Ziviani

I am a neuroscientist interested in the molecular mechanisms underlying defective mitophagy in neurodegenerative conditions, and approaches to normalize it. To this end, my group has become very interested in the biochemistry of action of deubiquitinating enzymes (DUBs) and small-molecule inhibitors of DUBs. Why DUBs? Mitophagy can be driven by ubiquitin ligases that reside on or are recruited to mitochondria to ubiquitinate mitochondrial proteins. These ligases can effectively be antagonized by specific DUBs, the inhibition of which proves to enhance mitophagy and to be protective in models of neurodegeneration. My group recently identified the DUB USP14, which we found to counteract MARCH5-dependent ubiquitination on its mitochondrial targets (PMID: 39486496). Inhibition of USP14 promotes mitochondrial ubiquitination and mitophagy, and substantially improves longevity and motor function of PINK1 and Parkin KO flies modeling PD (PMID: 30249595). The protective effect depends on the mitophagic effect of USP14 inhibition, which we also demonstrated in neurons of human origin (ref 2). More recently, we found that inhibition of USP14 abolishes sleep disturbances and circadian defects observed in PINK1 KO flies (PMID: 39486496) favoring the intriguing hypothesis that correction of circadian and sleep defects at prodromal phase may prevent or delay neuronal demise typical of the overt disease.