Phospholipids are imported into mitochondria by VDAC, a dimeric beta barrel scramblase

Abstract

Mitochondria are double-membrane-bounded organelles that depend critically on phospholipids supplied by the endoplasmic reticulum. These lipids must cross the outer membrane to support mitochondrial function, but how they do this is unclear. We identify the Voltage Dependent Anion Channel (VDAC), an abundant outer membrane protein, as a scramblase-type lipid transporter that catalyzes lipid entry. On reconstitution into membrane vesicles, dimers of human VDAC1 and VDAC2 catalyze rapid transbilayer translocation of phospholipids by a mechanism that is unrelated to their channel activity. Coarse-grained molecular dynamics simulations of VDAC1 reveal that lipid scrambling occurs at a specific dimer interface where polar residues induce large water defects and bilayer thinning. The rate of phospholipid import into yeast mitochondria is an order of magnitude lower in the absence of VDAC homologs, indicating that VDACs provide the main pathway for lipid entry. Thus, VDAC isoforms, members of a superfamily of beta barrel proteins, moonlight as a class of phospholipid scramblases - distinct from alpha-helical scramblase proteins - that act to import lipids into mitochondria.

Neurotoxic β-amyloid oligomers cause mitochondrial dysfunction—the trigger for PANoptosis in neurons

“…The mitochondrial permeability transition pore (mPTP), also known as the mitochondrial channel, is a channel between the inner and outer mitochondrial membranes that is composed of proteins. The mPTP is the basis for permeability transition; it consists mainly of the protein CypD, which is located in the matrix, the voltage-dependent anion channel (VDAC) located in the outer membrane, and the adenine nucleotide translocator (ANT) in the inner membrane (Jahn et al, 2023 ). Like most pore-forming toxins, AβO can induce perforation of neuronal and mitochondrial membranes; this is considered a mechanism of neurotoxicity induction and is observed in human AD patients (Lin et al, 2001 ; Lashuel et al, 2002 , 2003 ; Inoue, 2008 ; Tong et al, 2018 ).…”