Magri 2019 MiPschool Coimbra

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VDAC1 deletion in yeast affects mitochondrial DNA maintenance and promotes a metabolic rewiring towards fatty acids biosynthesis.

Link: MitoEAGLE

Magri A, Di Rosa MC, Orlandi I, Guarino F, Reina A, Messina A, Vai M, De Pinto V (2019)

Event: MiPschool Coimbra 2019

COST Action MitoEAGLE

The Voltage Dependent Anion-selective Channel (VDAC), known also as mitochondrial porin, represents the most abundant family of pore-forming protein in the Outer Mitochondrial Membrane (OMM) of all eukaryotes. Conserved from yeast to human, VDACs play a pivotal role in the metabolic cross-talk between cytosol and mitochondria, allowing metabolites and ions exchanges through OMM, in the regulation of apoptosis and in the interaction with cytosolic proteins in both physiological and pathological conditions [1]. In the budding yeast Saccharomyces cerevisiae the genetic inactivation of POR1 gene, encoding the main isoform VDAC1, produces defective growth in presence of non-fermentative substrate [2]. Yeast is endowed with a second porin gene, POR2, encoding VDAC2. Despite the latter is able to form channels in artificial membrane with properties resembling VDAC1 ones [3], VDAC2 is not able to compensate the absence of the main isoform since it is poorly expressed [4]. Nevertheless, VDAC1-null (Δpor1) cells are still viable. To better understand mechanisms behind this occurrence, the whole-genome expression of Δpor1 cells was characterized by microarray and the obtained data were validated by biochemical assays. Our results show that, in the absence of VDAC1, the expression of mitochondrial, but not nuclear, genes encoding oxidative phosphorylation chain subunits was completely abolished, as result of a dramatic decrease of mitochondrial DNA copies, with striking consequence for the organelle functionality. To overcome this condition, Δpor1 undergoes a complete metabolic rewiring that does not involve the activation of the retrograde response, as instead expected in case of mitochondrial dysfunction. In Δpor1, indeed, bypass pathways to target the substrates usually deployed to the mitochondria are enhanced and pyruvate is pushed towards cytosolic utilization by PDH by-pass rather than canonical mitochondrial uptake; then, units of acetyl-CoA are forwarded to the production of phospholipids, which in turn accumulate in lipid droplets, as an energy reservoir, and in the plasma membrane. Overall, our data suggest a key role of VDAC1 in the coordination of the entire cellular metabolism.


Bioblast editor: Plangger M


Labels: MiParea: mt-Membrane, mtDNA;mt-genetics, nDNA;cell genetics 


Organism: Saccharomyces cerevisiae 






Affiliations

Magrì A(1), Di Rosa MC(2), Orlandi I(3), Guarino F(2), Reina A(1), Messina A(1), Vai M(3), De Pinto V(2)
  1. Dept Biological, Geological, Environmental Sciences
  2. Dept Biomedical Biotechnological Sciences; Univ Catania
  3. Dept Biotechnologies Biosciences, Univ Milano-Bicocca; Italy. - andrea.magri@unict.it

References

  1. Magrì A, Reina S, De Pinto V (2018) VDAC1 as pharmacological target in cancer and neurodegeneration: focus on its role in apoptosis. Front Chem 6:108.
  2. Blachly-Dyson E, Song J, Wolfgang WJ, Colombini M, Forte M (1997) Multicopy suppressors of phenotypes resulting from the absence of yeast VDAC encode a VDAC-like protein. Mol Cell Biol 17:5727–38.
  3. Guardiani C, Magrì A, Karachitos A, Di Rosa MC, Reina S, Bodrenko I, Messina A, Kmita H, Ceccarelli M, De Pinto V (2018) yVDAC2, the second mitochondrial porin isoform of Saccharomyces cerevisiae. Biochim Biophys Acta Bioenerg 1859:270–79.
  4. Morgenstern M, Stiller SB, Lübbert P, Peikert CD, Dannenmaier S, Drepper F, Weill U, Höß P, Feuerstein R, Gebert M, Bohnert M, van der Laan M, Schuldiner M, Schütze C, Oeljeklaus S, Pfanner N, Wiedemann N, Warscheid B (2017) Definition of a high-confidence mitochondrial proteome at quantitative scale. Cell Rep 19:2836–52.