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TitleSmall molecule inhibition of voltage dependent anion channel 1 reroutes mitochondrial metabolite flux.
Journal, issue, pagesMol Cells, Vol. 49, Issue 7, Page 100369, Year 2026
Publish dateMay 13, 2026
AuthorsSeyed Majed Modaresi / Leilei Zhang / Amir Ata Saei / Morris Degen / Mohammad Khavani / Hassan Gharibi / Ákos Végvári / Zhiwei Ye / Jie Zhang / Evgeny Pavlov / Elizabeth A Jonas / Kenneth D Tew / Sebastian Hiller / Danyelle M Townsend / Eduardo N Maldonado /
PubMed AbstractVoltage dependent anion channels (VDACs 1, 2 and 3) in the outer mitochondrial membrane control the flux of anions and oxidizable substrates that sustain mitochondrial metabolism. Nicotinamide ...Voltage dependent anion channels (VDACs 1, 2 and 3) in the outer mitochondrial membrane control the flux of anions and oxidizable substrates that sustain mitochondrial metabolism. Nicotinamide adenine dinucleotide (NADH) closes VDAC by binding to a pocket, conserved in all isoforms, located in the inner wall of the channel. Previously, we identified the small molecule SC18 that targets the NADH-binding pocket of VDAC1 employing computational analysis. Here, we explored the interaction between SC18 and VDAC1 using high-resolution nuclear magnetic resonance spectroscopy and molecular dynamics simulations. Atomically resolved data precisely confirmed the computational results, showing that SC18 binds to a site on VDAC1 that partially overlaps with the NADH binding pocket. SC18, in the presence of NADH blocked the conductance of VDAC1 reconstituted in lipid bilayers. To determine the metabolic effect of SC18, we combined readouts of mitochondrial metabolism and glycolysis with functional metabolomics and proteomics. Short-term treatment with SC18 inhibited mitochondrial metabolism and adenosine triphosphate production. Treatment over 24 h and 48 h further reduced mitochondrial uptake of pyruvate and glutamine, utilization of tricarboxylic acid cycle intermediates, as well as lipid, DNA and amino acid synthesis. Concomitant with the inhibition of mitochondrial metabolism, cellular uptake of glucose and glutamine increased in parallel with augmented lactate release. These results indicate that compensatory enhanced glycolysis sustains adenosine triphosphate production after impaired mitochondrial function induced by SC18 blockage of VDAC1. Our work sets a mechanistic foundation for VDAC1 inhibition as a novel strategy to target and reprogram cancer metabolism through modulation of the biosynthetic ability of mitochondria.
External linksMol Cells / PubMed:42134653
MethodsEM (single particle)
Resolution5.4 Å
Structure data

71616

9pfz

EMDB-71616, PDB-9pfz:
Architecture of human Voltage Dependent Anion Channel 1 in nanodiscs
Method: EM (single particle) / Resolution: 5.4 Å

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / Beta-barrel / mitochondrial outer membrane protein / lipid bilayer nanodisc

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