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

• Published in: Cellular and molecular life sciences : CMLS Vol. 77; no. 16; pp. 3195 - 3213
• Main Authors: Magrì, Andrea, Di Rosa, Maria Carmela, Orlandi, Ivan, Guarino, Francesca, Reina, Simona, Guarnaccia, Maria, Morello, Giovanna, Spampinato, Antonio, Cavallaro, Sebastiano, Messina, Angela, Vai, Marina, De Pinto, Vito
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01-08-2020; Springer Nature B.V
• Subjects: Anions; Biochemistry; Bioenergetics; Biomedical and Life Sciences; Biomedicine; Biosynthesis; Carbon sources; Cell Biology; Cell size; Deactivation; Electric potential; Energy Metabolism - genetics; Energy Metabolism - physiology; Gene expression; Genes, Mitochondrial - genetics; Genomes; Glycolysis; Inactivation; Inositol; Intermediates; Ion channels; Life Sciences; Lipids; Malic enzyme; Membrane proteins; Metabolism; Metabolites; Mitochondria; Mitochondria - genetics; Mitochondria - metabolism; Mitochondrial DNA; Mitochondrial Membranes - metabolism; Original; Original Article; Oxidation-Reduction; Phospholipids; Pore formation; Porins - genetics; Porins - metabolism; Pyruvic acid; Rewiring; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - genetics; Saccharomyces cerevisiae Proteins - metabolism; Strain analysis; Tricarboxylic acid cycle; Vacuoles; Voltage; Voltage-Dependent Anion Channel 1 - genetics; Voltage-Dependent Anion Channel 1 - metabolism; Yeasts; PDH bypass; Inositol; Porin; Retrograde signaling; Mitochondrial DNA; Fatty acids; Warburg effect
• ISSN: 1420-682X; 1420-9071
• DOI: 10.1007/s00018-019-03342-8

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 (Δ
por1
) 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, Δ
por1
cells do not activate the rescue signaling retrograde response, as ρ
0
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, Δ
por1
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.