Ceramides bind VDAC2 to trigger mitochondrial apoptosis

Abstract

Ceramides draw wide attention as tumor suppressor lipids that act directly on mitochondria to trigger apoptotic cell death. However, molecular details of the underlying mechanism are largely unknown. Using a photoactivatable ceramide probe, we here identify the voltage-dependent anion channels VDAC1 and VDAC2 as mitochondrial ceramide binding proteins. Coarse-grain molecular dynamics simulations reveal that both channels harbor a ceramide binding site on one side of the barrel wall. This site includes a membrane-buried glutamate that mediates direct contact with the ceramide head group. Substitution or chemical modification of this residue abolishes photolabeling of both channels with the ceramide probe. Unlike VDAC1 removal, loss of VDAC2 or replacing its membrane-facing glutamate with glutamine renders human colon cancer cells largely resistant to ceramide-induced apoptosis. Collectively, our data support a role of VDAC2 as direct effector of ceramide-mediated cell death, providing a molecular framework for how ceramides exert their anti-neoplastic activity.

Defining how multiple lipid species interact with inward rectifier potassium (Kir2) channels

“…Calculation of residence times has been used in previous simulation studies to look at protein-water (71,72) and protein-lipid (15,(19)(20)(21)48) interactions. The residence time, θ, of a lipid type (e.g., PIP 2 or PS) is defined as the average time a single lipid headgroup spends continuously interacting with a Kir2.2.…”

“…In order to understand the kinetics of lipid interactions at the surface of Kir2.2 channels, the interaction time of each lipid headgroup at the surface is required. The residence time is a measure that has been used previously (15,(19)(20)(21)48). We calculated residence times for the distinct interaction sites identified using the analysis described above.…”

Mitochondria as intracellular signaling platforms in health and disease

“…Like cardiolipin, ceramide can also induce apoptosis by triggering BAX-dependent mitochondrial outer membrane permeabilization ( Birbes et al, 2001 ; Ganesan et al, 2010 ). Mechanistically, this may involve the direct targeting of voltage-dependent anion channel 2 (VDAC2) by ceramide ( Dadsena et al, 2019 ). In addition, during the initial phase of mitochondrial-mediated apoptosis, ceramide is further processed into two lipid messengers, sphingosine-1-phosphate and hexadecenal, which specifically activate Bcl-2 homologous antagonist killer (BAK) and BAX, respectively, for mitochondrial membrane permeabilization ( Chipuk et al, 2012 ).…”

Sphingolipids in Type 1 Diabetes: Focus on Beta-Cells

“…Cer contributes also to the suppression of mitochondrial electron transport chain and decreased ATP formation upon inflammation [76]. Recent studies identified the voltage-dependent anion channels VDAC1 and VDAC2 as mitochondrial ceramide binding proteins [77] and reported the expression of CerS within the mitochondrial compartment [77]. Moreover, the recent identification of a protein p17/PERMIT mediating ER-mitochondria tracking of newly translated CerS1 through MAMs to the mitochondrial outer membrane has been shown to be an event necessary for mitophagy induction [78].…”