Deletion of Voltage-Dependent Anion Channel 1 knocks mitochondria down triggering metabolic rewiring in yeast

Abstract

The Voltage-Dependent Anion-selective Channel (VDAC) is the pore-forming protein of mitochondrial outer membrane, allowing metabolites and ions exchanges. In Saccharomyces cerevisiae, inactivation of POR1, encoding VDAC1, produces defective growth in the presence of non-fermentable carbon source. Here, we characterized the whole-genome expression pattern of a VDAC1-null strain (Δpor1) by microarray analysis, discovering that the expression of mitochondrial genes was completely abolished, as consequence of the dramatic reduction of mtDNA. To overcome organelle dysfunction, Δpor1 cells do not activate the rescue signaling retrograde response, as ρ0 cells, and rather carry out complete metabolic rewiring. The TCA cycle works in a “branched” fashion, shunting intermediates towards mitochondrial pyruvate generation via malic enzyme, and the glycolysis-derived pyruvate is pushed towards cytosolic utilization by PDH bypass rather than the canonical mitochondrial uptake. Overall, Δpor1 cells enhance phospholipid biosynthesis, accumulate lipid droplets, increase vacuoles and cell size, overproduce and excrete inositol. Such unexpected re-arrangement of whole metabolism suggests a regulatory role of VDAC1 in cell bioenergetics.

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Acknowledgements

VDP acknowledges the financial support by MIUR (PRIN 2015795S5W_005) and University of Catania (Piano Triennale Ricerca). MV acknowledges the financial support by Cariplo Foundation 2015-0641. The authors acknowledge the support of Dr. Giulia Gentile for the initial experimental design of microarray analysis.

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Correspondence to Marina Vai or Vito De Pinto.

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Magrì, A., Di Rosa, M., Orlandi, I. et al. Deletion of Voltage-Dependent Anion Channel 1 knocks mitochondria down triggering metabolic rewiring in yeast. Cell. Mol. Life Sci. 77, 3195–3213 (2020). https://doi.org/10.1007/s00018-019-03342-8

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Keywords

  • Warburg effect
  • Inositol
  • Fatty acids
  • Porin
  • Retrograde signaling
  • PDH bypass
  • Mitochondrial DNA