Is the mitochondrial outermembrane protein VDAC1 therapeutic target for Alzheimer's disease?

Abstract

Mitochondrial dysfunction and synaptic damage have been described as early events in Alzheimer's disease (AD) pathogenesis. Recent research using AD postmortem brains, and AD mouse and cell models revealed that amyloid beta (Aβ) and tau hyperphosphorylation are involved in mitochondrial dysfunction and synaptic damage in AD. Further, recent research also revealed that the protein levels of mitochondrial outer membrane protein, voltage-dependent anion channel 1 (VDAC1), are elevated in the affected regions of AD postmortem brains and cortical tissues from APP transgenic mice. In addition, emerging research using AD postmortem brains and AD mouse models revealed that VDAC1 is linked to Aβ and phosphorylated tau, blocks the mitochondrial permeability transition (MPT) pores, disrupts the transport of mitochondrial proteins and metabolites, impairs gating of VDAC, and causes defects in oxidative phosphorylation, leading to mitochondrial dysfunction in AD neurons. The purpose of this article is to review research that has investigated the relationship between VDAC1 and the regulation of MPT pores in AD progression.

Figure 1

The structure of mitochondria. Mitochondria are compartmentalized into two biolipid membranes: the inner mitochondrial membrane and the outer mitochondrial membrane. The inner mitochondrial membrane houses the mitochondrial respiratory chain or electron transport chain (ETC) and provides a highly efficient barrier to ionic flow. In the ETC - complexes I, III leak electrons to oxygen, producing primarily superoxide radicals, and superoxide radicals are dismutated by manganese superoxide dismuase and produce H₂O₂. Further, ETC involves the reduction of H₂O₂ to H₂O and O₂ by catalase or glutathione peroxidase accepting electrons donated by NADH and FADH₂ and then yielding energy for the generation of ATP from adenosine diphosphate and inorganic phosphate.

Figure 2

Schematic representation of mitochondrial permeability transition pore opening and closure. In an open state of mitochondrial permeability transition pore, metabolites, including ADP/ATP, inorganic phosphate, pyruvate and other substrates and ions, enter and leave mitochondria after passing through the outer mitochondrial membrane. In a closed state, VDAC does not allow the regular flow of ADP/ATP through the outer membrane.

Figure 3

The structure of human VDAC gene. The human VDAC gene has 3 isoforms; isoform 1 or VDAC1 has 9 exons with a start codon, ATG in exon 2 and a long polyadenylation site. Isoform 2 and VDAC2 has 10 exons with multiple polyadenylation sites, and isoform 3 has 3 has 9 exons. VDAC1 has 2 splice variants, and VDAC2 and VDAC3 each have one splice variant.

Figure 4

VDACs perform multiple functions – 1) regulating cell survival and cell growth, 2) fertility; 3) maintaining synaptic plasticity through MPT pore, 4) regulating calcium transport, 5) regulating ATP transport, 6) regulating mitochondrial shape and structural changes, 7) regulating hexokinase interactions with mitochondria and 8) regulating apoptosis signaling.