bims-tofagi 2024-12-29 papers

Issue of 2024–12–29
three papers selected by
Michele Frison, University of Cambridge and Aitor Martínez Zarate, Euskal Herriko Unibertsitatea

Nat Commun. 2024 Dec 23. 15(1): 10719

Preventing excessive autophagy protects from the pathology of mtDNA mutations in Drosophila melanogaster.

Najla El Fissi, Florian A Rosenberger, Kai Chang, Alissa Wilhalm, Tom Barton-Owen, Fynn M Hansen, Zoe Golder, David Alsina, Anna Wedell, Matthias Mann, Patrick F Chinnery, Christoph Freyer, Anna Wredenberg.

Aberration of mitochondrial function is a shared feature of many human pathologies, characterised by changes in metabolic flux, cellular energetics, morphology, composition, and dynamics of the mitochondrial network. While some of these changes serve as compensatory mechanisms to maintain cellular homeostasis, their chronic activation can permanently affect cellular metabolism and signalling, ultimately impairing cell function. Here, we use a Drosophila melanogaster model expressing a proofreading-deficient mtDNA polymerase (POLγexo-) in a genetic screen to find genes that mitigate the harmful accumulation of mtDNA mutations. We identify critical pathways associated with nutrient sensing, insulin signalling, mitochondrial protein import, and autophagy that can rescue the lethal phenotype of the POLγexo- flies. Rescued flies, hemizygous for dilp1, atg2, tim14 or melted, normalise their autophagic flux and proteasome function and adapt their metabolism. Mutation frequencies remain high with the exception of melted-rescued flies, suggesting that melted may act early in development. Treating POLγexo- larvae with the autophagy activator rapamycin aggravates their lethal phenotype, highlighting that excessive autophagy can significantly contribute to the pathophysiology of mitochondrial diseases. Moreover, we show that the nucleation process of autophagy is a critical target for intervention.

DOI: https://doi.org/10.1038/s41467-024-55559-2

Autophagy. 2024 Dec 27.

Reconsidering the selectivity of bulk autophagy: cargo hitchhiking specifies cargo for degradation.

Eigo Takeda, Alexander I May, Yoshinori Ohsumi.

Bulk macroautophagy/autophagy, typically induced by starvation, is generally thought to non-selectively isolate cytosolic components for degradation. However, a detailed analysis of bulk autophagy cargo has not been conducted. We recently employed mass spectrometry to analyze the contents of isolated autophagic bodies. In this process, we uncovered Hab1 (Highly enriched in Autophagic Bodies 1), a novel protein, that is preferentially delivered via autophagy. Hab1 is a receptor protein that binds Atg8-PE and ribosomes at its N- and C-termini, respectively. We found that ribosome-bound Hab1 is preferentially delivered to the vacuole by "'hitchhiking'" on phagophores/isolation membranes formed during bulk autophagy. This hitchhiking mechanism confers selectivity to bulk autophagy.

Keywords: Atg8; Hab1; Saccharomyces cerevisiae; hitchhiking; ribosome

DOI: https://doi.org/10.1080/15548627.2024.2447209

Am J Hum Genet. 2024 Dec 24. pii: S0002-9297(24)00418-X. [Epub ahead of print]

Heterozygous UBR5 variants result in a neurodevelopmental syndrome with developmental delay, autism, and intellectual disability.

Pascale Sabeh, Samantha A Dumas, Claudia Maios, Hiba Daghar, Marek Korzeniowski, Justine Rousseau, Matthew Lines, Andrea Guerin, John J Millichap, Megan Landsverk, Theresa Grebe, Kristin Lindstrom, Jonathan Strober, Tarik Ait Mouhoub, Christiane Zweier, Michelle Steinraths, Moritz Hebebrand, Bert Callewaert, Rami Abou Jamra, Monika Kautza-Lucht, Meret Wegler, Paul Kruszka, Candy Kumps, Ehud Banne, Marta Biderman Waberski, Anne Dieux, Sarah Raible, Ian Krantz, Livija Medne, Kieran Pechter, Laurent Villard, Renzo Guerrini, Claudia Bianchini, Carmen Barba, Davide Mei, Xavier Blanc, Christine Kallay, Emmanuelle Ranza, Xiao-Ru Yang, Emily O'Heir, Kirsten A Donald, Serini Murugasen, Zandre Bruwer, Muge Calikoglu, Jennifer M Mathews, Marion Lesieur-Sebellin, Geneviève Baujat, Nicolas Derive, Tyler Mark Pierson, Jill R Murrell, Amelle Shillington, Clothilde Ormieres, Sophie Rondeau, André Reis, Alberto Fernandez-Jaen, Ping Yee Billie Au, David A Sweetser, Lauren C Briere, Nathalie Couque, Laurence Perrin, Jennifer Schymick, Paul Gueguen, Mathilde Lefebvre, Michael Van Andel, Jane Juusola, Stylianos E Antonarakis, J Alex Parker, Barrington G Burnett, Philippe M Campeau.

E3 ubiquitin ligases have been linked to developmental diseases including autism, Angelman syndrome (UBE3A), and Johanson-Blizzard syndrome (JBS) (UBR1). Here, we report variants in the E3 ligase UBR5 in 29 individuals presenting with a neurodevelopmental syndrome that includes developmental delay, autism, intellectual disability, epilepsy, movement disorders, and/or genital anomalies. Their phenotype is distinct from JBS due to the absence of exocrine pancreatic insufficiency and the presence of autism, epilepsy, and, in some probands, a movement disorder. E3 ubiquitin ligases are responsible for transferring ubiquitin to substrate proteins to regulate a variety of cellular functions, including protein degradation, protein-protein interactions, and protein localization. Knocking out ubr-5 in C. elegans resulted in a lower movement score compared to the wild type, supporting a role for UBR5 in neurodevelopment. Using an in vitro autoubiquitination assay and confocal microscopy for the human protein, we found decreased ubiquitination activity and altered cellular localization in several variants found in our cohort compared to the wild type. In conclusion, we found that variants in UBR5 cause a neurodevelopmental syndrome that can be associated with a movement disorder, reinforcing the role of the UBR protein family in a neurodevelopmental disease that differs from previously described ubiquitin-ligase-related syndromes. We also provide evidence for the pathogenic potential loss of UBR5 function with functional experiments in C. elegans and in vitro ubiquitination assays.

Keywords: Mendelian phenotype; UBR5; autism; autosomal dominant; developmental disease; epilepsy; intellectual disability; movement disorders; ubiquitin

DOI: https://doi.org/10.1016/j.ajhg.2024.11.009