VDAC1 Knockout Affects Mitochondrial Oxygen Consumption Triggering a Rearrangement of ETC by Impacting on Complex I Activity

Int J Mol Sci. 2023 Feb 12;24(4):3687. doi: 10.3390/ijms24043687.

Abstract

Voltage-Dependent Anion-selective Channel isoform 1 (VDAC1) is the most abundant isoform of the outer mitochondrial membrane (OMM) porins and the principal gate for ions and metabolites to and from the organelle. VDAC1 is also involved in a number of additional functions, such as the regulation of apoptosis. Although the protein is not directly involved in mitochondrial respiration, its deletion in yeast triggers a complete rewiring of the whole cell metabolism, with the inactivation of the main mitochondrial functions. In this work, we analyzed in detail the impact of VDAC1 knockout on mitochondrial respiration in the near-haploid human cell line HAP1. Results indicate that, despite the presence of other VDAC isoforms in the cell, the inactivation of VDAC1 correlates with a dramatic impairment in oxygen consumption and a re-organization of the relative contributions of the electron transport chain (ETC) enzymes. Precisely, in VDAC1 knockout HAP1 cells, the complex I-linked respiration (N-pathway) is increased by drawing resources from respiratory reserves. Overall, the data reported here strengthen the key role of VDAC1 as a general regulator of mitochondrial metabolism.

Keywords: HAP1 cells; VDAC1 knockout; complex I; mitochondria; respiratory reserve(s).

MeSH terms

  • Electron Transport Complex I* / metabolism
  • Electron Transport Complex I* / physiology
  • Humans
  • Mitochondria* / metabolism
  • Mitochondrial Membranes / metabolism
  • Oxygen Consumption* / genetics
  • Porins / metabolism
  • Protein Isoforms / metabolism
  • Saccharomyces cerevisiae / metabolism
  • Voltage-Dependent Anion Channel 1* / genetics
  • Voltage-Dependent Anion Channel 1* / metabolism

Substances

  • Electron Transport Complex I
  • Porins
  • Protein Isoforms
  • VDAC1 protein, human
  • Voltage-Dependent Anion Channel 1

Grants and funding

This research was funded by PIACERI (grant no. ARVEST) and Proof of Concept (grant no. PEPSLA POC 01_00054), awarded to A. Messina, and PIACERI (grant no. VDAC) and CHANCE, awarded to to V.D.P.