Metabolic rewiring and autophagy inhibition correct lysosomal storage disease in mucopolysaccharidosis IIIB

Melania Scarcella; Gianluca Scerra; Mariangela Ciampa; Marianna Caterino; Michele Costanzo; Laura Rinaldi; Antonio Feliciello; Serenella Anzilotti; Chiara Fiorentino; Maurizio Renna; Margherita Ruoppolo; Luigi Michele Pavone; Massimo D'Agostino; Valeria De Pasquale

doi:10.1016/j.isci.2024.108959

Metabolic rewiring and autophagy inhibition correct lysosomal storage disease in mucopolysaccharidosis IIIB

iScience. 2024 Jan 29;27(3):108959. doi: 10.1016/j.isci.2024.108959. eCollection 2024 Mar 15.

Authors

Melania Scarcella¹, Gianluca Scerra¹, Mariangela Ciampa¹, Marianna Caterino^{1

2}, Michele Costanzo^{1

2}, Laura Rinaldi¹, Antonio Feliciello¹, Serenella Anzilotti³, Chiara Fiorentino¹, Maurizio Renna¹, Margherita Ruoppolo^{1

2}, Luigi Michele Pavone¹, Massimo D'Agostino¹, Valeria De Pasquale⁴

Affiliations

¹ Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy.
² CEINGE Biotecnologie Avanzate Franco Salvatore, Via G. Salvatore 486, 80131 Naples, Italy.
³ Department of Science and Technology, University of Sannio, Via F. de Sanctis, 82100 Benevento, Italy.
⁴ Department of Veterinary Medicine and Animal Productions, University of Naples Federico II, Via F. Delpino 1, 80137 Naples, Italy.

Abstract

Mucopolysaccharidoses (MPSs) are lysosomal disorders with neurological involvement for which no cure exists. Here, we show that recombinant NK1 fragment of hepatocyte growth factor rescues substrate accumulation and lysosomal defects in MPS I, IIIA and IIIB patient fibroblasts. We investigated PI3K/Akt pathway, which is of crucial importance for neuronal function and survival, and demonstrate that PI3K inhibition abolishes NK1 therapeutic effects. We identified that autophagy inhibition, by Beclin1 silencing, reduces MPS IIIB phenotype and that NK1 downregulates autophagic-lysosome (ALP) gene expression, suggesting a possible contribution of autophagosome biogenesis in MPS. Indeed, metabolomic analyses revealed defects of mitochondrial activity accompanied by anaerobic metabolism and inhibition of AMP-activated protein kinase (AMPK), which acts on metabolism and autophagy, rescues lysosomal defects. These results provide insights into the molecular mechanisms of MPS IIIB physiopathology, supporting the development of new promising approaches based on autophagy inhibition and metabolic rewiring to correct lysosomal pathology in MPSs.

Keywords: Cell biology; Human metabolism.