Small Hexokinase 1 Peptide against Toxic SOD1 G93A Mitochondrial Accumulation in ALS Rescues the ATP-Related Respiration

Biomedicines

Beatrice Formicola¹  Francesca Re¹  Andrea Magrì²  Stefania Zimbone²  Angela Messina²  Cristina Arrigoni³  Pierpaolo Risiglione⁴  Antonella Caccamo⁵  Marianna Flora Tomasello⁶  Francesca Guarino⁷ 

[1] BioNanoMedicine Center NANOMIB, School of Medicine & Surgery, University of Milano-Bicocca, Via Cadore 48, 20900 Monza, Italy;Department of Biological, Geological and Environmental Sciences, University of Catania, Via S. Sofia 64, 95123 Catania, Italy;Department of Biology and Biotechnology, University of Pavia, Via Ferrata 9, 27100 Pavia, Italy;Department of Biomedical and Biotechnological Sciences, University of Catania, Via S. Sofia 64, 95123 Catania, Italy;Department of Drug and Health Sciences, University of Catania, Via S. Sofia 64, 95123 Catania, Italy;Istituto di Cristallografia, CNR, Via Paolo Gaifami 18, 95126 Catania, Italy;we.MitoBiotech S.R.L., C.so Italia 172, 95125 Catania, Italy;

关键词: amyotrophic lateral sclerosis;    SOD1;    VDAC1;    hexokinase;    mitochondria;    interfering peptide;   

DOI  :  10.3390/biomedicines9080948

来源: DOAJ

【 摘 要 】

Mutations in Cu/Zn Superoxide Dismutase (SOD1) gene represent one of the most common causes of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder that specifically affects motor neurons (MNs). The dismutase-active SOD1 G93A mutant is responsible for the formation of toxic aggregates onto the mitochondrial surface, using the Voltage-Dependent Anion Channel 1 (VDAC1) as an anchor point to the organelle. VDAC1 is the master regulator of cellular bioenergetics and by binding to hexokinases (HKs) it controls apoptosis. In ALS, however, SOD1 G93A impairs VDAC1 activity and displaces HK1 from mitochondria, promoting organelle dysfunction, and cell death. Using an ALS cell model, we demonstrate that a small synthetic peptide derived from the HK1 sequence (NHK1) recovers the cell viability in a dose–response manner and the defective mitochondrial respiration profile relative to the ADP phosphorylation. This correlates with an unexpected increase of VDAC1 expression and a reduction of SOD1 mutant accumulation at the mitochondrial level. Overall, our findings provide important new insights into the development of therapeutic molecules to fight ALS and help to better define the link between altered mitochondrial metabolism and MNs death in the disease.

【 授权许可】

Unknown