Warburg Revisited: Regulation of Mitochondrial Metabolism by Voltage-Dependent Anion Channels in Cancer Cells

Abstract

The bioenergetics of cancer cells is characterized by a high rate of aerobic glycolysis and suppression of mitochondrial metabolism (Warburg phenomenon). Mitochondrial metabolism requires inward and outward flux of hydrophilic metabolites, including ATP, ADP and respiratory substrates, through voltage-dependent anion channels (VDACs) in the mitochondrial outer membrane. Although VDACs were once considered to be constitutively open, closure of the VDAC is emerging as an adjustable limiter (governator) of mitochondrial metabolism. Studies of VDACs reconstituted into planar lipid bilayers show that tubulin at nanomolar concentrations decreases VDAC conductance. In tumor cell lines, microtubule-destabilizing agents increase cytoplasmic free tubulin and decrease mitochondrial membrane potential (⌬⌿ m ), whereas microtubule stabilization increases ⌬⌿ m . Tubulin-dependent suppression of ⌬⌿ m is further potentiated by protein kinase A activation and glycogen synthase kinase-3␤ inhibition. Knockdown of different VDAC isoforms, especially of the least abundant isoform, VDAC3, also decreases ⌬⌿ m , cellular ATP, and NADH/NAD ϩ , suggesting that VDAC1 and VDAC2 are most inhibited by free tubulin. The brake on mitochondrial metabolism imposed by the VDAC governator probably is released when spindles form and free tubulin decreases as cells enter mitosis, which better provides for the high ATP demands of chromosome separation and cytokinesis. In conclusion, tubulin-dependent closure of VDACs represents a new mechanism contributing to the suppression of mitochondrial metabolism in the Warburg phenomenon.

Novel function of ceramide for regulation of mitochondrial ATP release in astrocytes

“…This observation is quite remarkable since this assay does not distinguish between mitochondrial or cytosolic ATP levels, indicating that blocking VDAC1 will reduce both ATP pools. It should be by guest, on May 11, 2018 www.jlr.org There is some discrepancy in which VDAC isoform is more critical for regulation of intracellular ATP, which is likely to be cell-type specific (51,52). Most recently, excess elevation of ceramide has been shown to induce mitophagy, suggesting that the physiological function of ceramide as discussed in our study requires limitation of its concentration at mitochondria (88,89).…”

“…In astrocytes, VDAC1 is critical for secretion of ATP, a gliotransmitter regulating synaptic plasticity and neuronal function (47)(48)(49)(50). Most recently, VDAC1 closure by tubulin has been suggested to be critical for the Warburg effect, a metabolic switch from mitochondria-mediated oxidative phosphorylation to glycolysis for ATP production, often observed in cancer cells (51)(52)(53).…”

Sequence diversity of tubulin isotypes in regulation of the mitochondrial voltage-dependent anion channel

“…It was proposed that tubulin's interaction with VDAC contributes to suppression of mitochondrial metabolism in the Warburg phenomenon (30).…”

Voltage-dependent Anion Channels Modulate Mitochondrial Metabolism in Cancer Cells

“…VDAC in its open state is permeable to ATP, ADP, and respiratory substrates. Although VDAC is generally considered to be constitutively open in aerobic cells, partial closure of VDAC has been proposed to account, in part, for the suppression of mitochondrial metabolism in the Warburg phenomenon (9,21,22).…”