Hexokinase I N-terminal based peptide prevents the VDAC1-SOD1 G93A interaction and re-establishes ALS cell viability

Abstract

Superoxide Dismutase 1 mutants associate with 20–25% of familial Amyotrophic Lateral Sclerosis (ALS) cases, producing toxic aggregates on mitochondria, notably in spinal cord. The Voltage Dependent Anion Channel isoform 1 (VDAC1) in the outer mitochondrial membrane is a docking site for SOD1 G93A mutant in ALS mice and the physiological receptor of Hexokinase I (HK1), which is poorly expressed in mouse spinal cord. Our results demonstrate that HK1 competes with SOD1 G93A for binding VDAC1, suggesting that in ALS spinal cord the available HK1-binding sites could be used by SOD1 mutants for docking mitochondria, producing thus organelle dysfunction. We tested this model by studying the action of a HK1-N-terminal based peptide (NHK1). This NHK1 peptide specifically interacts with VDAC1, inhibits the SOD1 G93A binding to mitochondria and restores the viability of ALS model NSC34 cells. Altogether, our results suggest that NHK1 peptide could be developed as a therapeutic tool in ALS, predicting an effective role also in other proteinopathies.

Proteinopathies and OXPHOS dysfunction in neurodegenerative diseases

“…Interactions with VDAC were proposed to alter the properties of the channel and impede ATP and ADP flow ( Israelson et al, 2010 ). In addition, SOD1 competes with hexokinase 1 for binding to VDAC, thereby displacing the enzyme from the OM ( Magrì et al, 2016 ). The SOD1–Bcl-2 interactions were also proposed to inhibit the ADP entry into mitochondria and to cause an increase in mitochondrial membrane potential because of loss of ADP phosphorylation by the ATPase ( Tan et al, 2013 ).…”

Recombinant yeast VDAC2: a comparison of electrophysiological features with the native form

“…Since membrane proteins localize into inclusion bodies, bacterial lysis occurred upon denaturing conditions, with the loss of the native conformation. Therefore, once isolated, in order to obtain a perfectly active protein, the recombinant protein must undergo a refolding procedure using a wellestablished protocol [11,[19][20][21][22].…”

VDAC3 As a Potential Marker of Mitochondrial Status Is Involved in Cancer and Pathology

“…VCP is a member of the ERAD pathway and is involved in the “extraction” of protein from the OMM and other membranes to be directed to ubiquitination and degradation through ER, with or without stress conditions (64). VCP mutants have been correlated to the onset of some type of myopathies, of frontotemporal dementia and of Alzheimer disease, Parkinson’s disease, or amyotrophic lateral sclerosis, all pathologies where VDAC involvement has been already reported (71–74). VCP could be in charge of extracting the modified version of VDAC3, addressing it toward microtubules through cytoplasmic granules’ traffic (62) and enriching near the centrosome.…”