The Biogenesis Process of VDAC – From Early Cytosolic Events to Its Final Membrane Integration

Abstract

Voltage dependent anion-selective channel (VDAC) is the most abundant protein in the mitochondrial outer membrane. It is a membrane embedded β-barrel protein composed of 19 mostly anti-parallel β-strands that form a hydrophilic pore. Similar to the vast majority of mitochondrial proteins, VDAC is encoded by nuclear DNA, and synthesized on cytosolic ribosomes. The protein is then targeted to the mitochondria while being maintained in an import competent conformation by specific cytosolic factors. Recent studies, using yeast cells as a model system, have unearthed the long searched for mitochondrial targeting signal for VDAC and the role of cytosolic chaperones and mitochondrial import machineries in its proper biogenesis. In this review, we summarize our current knowledge regarding the early cytosolic stages of the biogenesis of VDAC molecules, the specific targeting of VDAC to the mitochondrial surface, and the subsequent integration of VDAC into the mitochondrial outer membrane by the TOM and TOB/SAM complexes.

Mitochondrial protein translocation machinery: From TOM structural biogenesis to functional regulation

“…The vital components for the import and assembly of mOMPs are the TOM complex, IMS small Tim chaperones (holdases), and the SAM complex ( 2 , 5 , 8 , 9 , 79 , 82 , 83 , 88 , 133 , 134 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 ). All β-barrel precursors carry a noncleavable amphipathic internal targeting signal sequence located in the last β-hairpin of the mOMP ( 79 , 143 , 144 , 145 , 146 ).…”

“…The vital components for the import and assembly of mOMPs are the TOM complex, IMS small Tim chaperones (holdases), and the SAM complex ( 2 , 5 , 8 , 9 , 79 , 82 , 83 , 88 , 133 , 134 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 ). All β-barrel precursors carry a noncleavable amphipathic internal targeting signal sequence located in the last β-hairpin of the mOMP ( 79 , 143 , 144 , 145 , 146 ). This noncleavable signal usually contains the consensus sequence PxGhxHxH (P: polar; G: Gly; h: hydrophobic aliphatic; H: hydrophobic aromatic) ( 88 , 146 , 147 ) and relates evolutionarily to the bacterial β-barrel proteins ( 8 , 9 , 145 ).…”

“…The import process begins with the interaction of the β-barrel polypeptide with the Tom70 and Tom22 receptors ( Fig. 4 ), followed by translocation through the hydrophobic patch of the Tom40 channel ( 83 , 143 , 148 ). As the polypeptide enters the IMS, the small Tim chaperones Tim9–Tim10 bind and transport the protein to the SAM complex ( 56 , 80 , 133 , 134 , 149 ).…”

Historical Perspective of Pore-Forming Activity Studies of Voltage-Dependent Anion Channel (Eukaryotic or Mitochondrial Porin) Since Its Discovery in the 70th of the Last Century

“…This suggests that since the event of endosymbiosis about 1–2 billion years ago many genes of the protomitochondrion came under control of the eukaryotic host. The mitochondrial proteins produced in the cytoplasm of the host cells are imported via the mitochondrial outer membrane import TOM complex into the intermembrane space using a not yet fully identified import signal, which is presumably related to the β-strands of the imported proteins ( Bausewein et al, 2020 ; Drwesh and Rapaport, 2020 ; Moitra and Rapaport, 2021 ). This is based on the observation that the β-hairpin element of eukaryotic porins interacts with the mitochondrial import receptor Tom20 ( Jores et al, 2016 ).…”

“…This is based on the observation that the β-hairpin element of eukaryotic porins interacts with the mitochondrial import receptor Tom20 ( Jores et al, 2016 ). From there, the mitochondrial outer membrane proteins are assembled by the multi-subunit TOB/SAM system (sorting and assembly machinery) in the mitochondrial outer membrane with the help of the hexamer of the small TIM chaperones ( Moitra and Rapaport, 2021 ). The SAM system has a high homology to the barrel-assembly machinery BAM of Gram-negative bacteria, which provides also evidence that Gram-negative bacteria were ancestors of mitochondria ( Pereira and Lupas, 2018 ; Diederichs et al, 2020 , 2021 ; Takeda et al, 2021 ).…”