Magri 2022 Abstract Bioblast
8.5. «5 min» Magrì Andrea, Cubisino SAM, De Pinto V, Messina A (2022) Modulation of mitochondrial respiration in ALS cells by hexokinase-based peptides: a novel therapeutic approach to fight neurodegeneration. Bioblast 2022: BEC Inaugural Conference. In: https://doi.org/10.26124/bec:2022-0001 |
Link: Bioblast 2022: BEC Inaugural Conference
Magri Andrea, Cubisino SAM, De Pinto Vito, Messina Angela (2022)
Event: Bioblast 2022
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease which affects motor neurons (MNs). Many familial and sporadic forms correlate with mutations in the gene encoding the antioxidant enzyme Cu/Zn Superoxide Dismutase (SOD1). Among mutants, the dismutase-active SOD1 G93A forms toxic aggregates on the cytosolic surface of outer mitochondrial membrane (OMM), using the Voltage-Dependent Anion Channel 1 (VDAC1) as binding site [1]. VDAC1 is the most abundant OMM pore-forming protein and allows the trafficking of metabolites (pyruvate, malate), ions, NAD+/NADH and ATP/ADP across the membrane; furthermore, it serves as an anchor for many cytosolic proteins, mostly for Hexokinases (HKs) [2]. However, in ALS MNs, the mitochondrial accumulation of SOD1 G93A impairs molecules exchange through VDAC1 and displaces HKs from mitochondria, promoting the organelle dysfunction and cell death [1-2].
By a means of in vitro and in cellulo approaches, we previously demonstrated that HK1 and SOD1 G93A compete for the same mitochondrial binding site, VDAC1 [3]. Based on these observations, we developed a small synthetic peptide corresponding to the first 11 amino acid residues of the HK1 N-terminal domain (NHK1) [3]. NHK1 is able to modulates VDAC1 activity when it is reconstituted in artificial membranes; when added to ALS MNs, the peptide promotes a complete recovery of the cell viability in a dose-response manner [3-4]. By using High-Resolution Respirometry (HRR), we then analyzed the mitochondrial respiration profile of MN-like cells NSC34 stably expressing SOD1 G93A. Our results indicate that NHK1 promotes a partial increase of oxygen consumption corresponding to ROUTINE and OXPHOS state. As demonstrated by FCRs analysis, the peptide stimulates a significative decrease of the LEAK respiration while increases net respiration and coupling efficiency linked to OXPHOS state [4]. This effect is probably due to the reduction of ~70 % of VDAC1-SOD1 G93A aggregates observed in the mitochondrial fraction of cells treated with NHK1 [4].
In conclusion, our results suggest that NHK1 drives the recovery of compromised mitochondrial respiration typical of ALS and provide new insights into the development of therapeutic molecules to fight the disease. Overall, our work helps to better understand the relationship between altered mitochondrial metabolism and MNs death.
- Israelson A, Arbel N, da Cruz S, Ilieva H, Yamanaka K, Shoshan-Barmatz V, Cleveland DW (2010) Misfolded mutant SOD1 directly inhibits VDAC1 conductance in a mouse model of inherited ALS. https://doi.org/10.1016/j.neuron.2010.07.019
- Magrì A, Reina S, De Pinto V (2018) VDAC1 as pharmacological target in cancer and neurodegeneration: focus on its role in apoptosis. https://doi.org/10.3389/fchem.2018.00108
- Magrì A, Belfiore R, Reina S, Tomasello MF, Di Rosa MC, Guarino F, Leggio L, De Pinto V, Messina A (2016) Hexokinase I N-terminal based peptide prevents the VDAC1-SOD1 G93A interaction and re-establishes ALS cell viability. https://doi.org/10.1038/srep34802
- Magrì A, Risiglione P, Caccamo A, Formicola B, Tomasello MF, Arrigoni C, Zimbone S, Guarino F, Re F, Messina A (2021) Small Hexokinase 1 peptide against toxic SOD1 G93A mitochondrial accumulation in ALS rescues the ATP-related respiration. https://doi.org/10.3390/biomedicines9080948
• Bioblast editor: Plangger M
• O2k-Network Lab: IT Catania Messina A
Affiliations
- Magrì A1,2, Cubisino SAM3, De Pinto V2,3, Messina A1,2
- Dept Biological, Geological, Environmental Sciences, Univ of Catania, Italy - [email protected]
- we.MirtoBiotech s.r.l., Catania, Italy
- Dept Biomedical and Biotechnological Sciences, Univ of Catania, Italy
Figures
List of abbreviations, terms and definitions - MitoPedia
Labels: MiParea: Respiration, mt-Membrane
Pathology: Neurodegenerative
Organism: Human Tissue;cell: Nervous system Preparation: Permeabilized cells, Intact cells
Coupling state: LEAK, ROUTINE, OXPHOS, ET
Pathway: N, S, NS, ROX
HRR: Oxygraph-2k
Event: B4