Small hexokinase 1 peptide against toxic sod1 g93a mitochondrial accumulation in als rescues the atp-related respiration

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