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

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.

VDAC1-interacting molecules promote cell death in cancer organoids through mitochondrial-dependent metabolic interference

“…Except for some compensatory effect given by other isoforms, the inactivation of VDAC1 gene triggers a re-arrangement of the electron transport system functioning. 48 , 49 Therefore, targeting the major mitochondrial metabolite transporter VDAC1 could represent a promising strategy since the channel is involved in many cancer processes, i.e., the inhibition of apoptosis, and it is considered the “mitochondrial gate keeper” because of its role in metabolite translocation from the cytosol to the mitochondria and vice-versa. However, most of the identified molecules are either not specific, with undesired side effects on channel function, or biochemically poorly characterized, 19 , 32 , 50 , 51 lowering the chances for a further pharmaceutical development.…”

“…The oxygen flows linked to ATP production were calculated as the difference between the NS-pathway and the LEAK respiration. 48 Respiratory states of cells exposed to VA molecules were normalized to their respective untreated controls and shown as mean ± SEM of n=3 in three independent experiments. Data were statistically analyzed by unpaired t-test using Prism software (GraphPad, San Diego, CA, co USA).…”

VDAC1 selective molecules promote patients’-derived cancer organoids death through mitochondrial-dependent metabolic interference

“…Except for some compensatory effect given by other isoforms, the inactivation of VDAC1 gene triggers a re-arrangement of the electron transport system functioning (Magri et al, 2023a). Where VDAC1 represents the only functional porin, as in yeast, its deletion even prompts the mitochondrial switch off and a complete metabolic rewiring aimed at bypassing the organelle dysfunction (Magri et al, 2020).…”

“…Rather than just a mere channel, VDAC1 figures as a molecular switch for the modulation of the cell bioenergetics and links glycolysis to mitochondrial metabolism by its direct interaction with HKs. Except for some compensatory effect given by other isoforms, the inactivation of VDAC1 gene triggers a re-arrangement of the electron transport system functioning (Magri et al, 2023a). Where VDAC1 represents the only functional porin, as in yeast, its deletion even prompts the mitochondrial switch off and a complete metabolic rewiring aimed at bypassing the organelle dysfunction (Magri et al, 2020).…”

Solute Transport through Mitochondrial Porins In Vitro and In Vivo

“…The yield of oxidative phosphorylation is more than 30 moles of ATP per mole glucose, which means that it is much higher compared with glycolysis. Mitochondrial porins are considered governors or gatekeepers of mitochondrial metabolism in these processes, which are supported by the effects of porin deletions [ 24 , 121 , 162 , 163 , 164 , 165 , 166 , 167 , 168 , 169 ].…”