The Voltage-dependent Anion Channel 1 Mediates Amyloid β Toxicity and Represents a Potential Target for Alzheimer Disease Therapy

Abstract

The voltage-dependent anion channel 1 (VDAC1), found in the mitochondrial outer membrane, forms the main interface between mitochondrial and cellular metabolisms, mediates the passage of a variety of molecules across the mitochondrial outer membrane, and is central to mitochondria-mediated apoptosis. VDAC1 is overexpressed in post-mortem brains of Alzheimer disease (AD) patients. The development and progress of AD are associated with mitochondrial dysfunction resulting from the cytotoxic effects of accumulated amyloid ␤ (A␤). In this study we demonstrate the involvement of VDAC1 and a VDAC1 N-terminal peptide (VDAC1-N-Ter) in A␤ cell penetration and cell death induction. A␤ directly interacted with VDAC1 and VDAC1-N-Ter, as monitored by VDAC1 channel conductance, surface plasmon resonance, and microscale thermophoresis. Preincubated A␤ interacted with bilayer-reconstituted VDAC1 and increased its conductance ϳ2-fold. Incubation of cells with A␤ resulted in mitochondria-mediated apoptotic cell death. However, the presence of non-cell-penetrating VDAC1-N-Ter peptide prevented A␤ cellular entry and A␤-induced mitochondria-mediated apoptosis. Likewise, silencing VDAC1 expression by specific siRNA prevented A␤ entry into the cytosol as well as A␤-induced toxicity. Finally, the mode of A␤-mediated action involves detachment of mitochondria-bound hexokinase, induction of VDAC1 oligomerization, and cytochrome c release, a sequence of events leading to apoptosis. As such, we suggest that A␤-mediated toxicity involves mitochondrial and plasma membrane VDAC1, leading to mitochondrial dysfunction and apoptosis induction. The VDAC1-N-Ter peptide targeting A␤ cytotoxicity is thus a potential new therapeutic strategy for AD treatment. Alzheimer disease (AD)3 pathology is characterized by cognitive decline, brain synaptic dysfunction, inflammatory responses, and mitochondrial dysfunction (1). The aggregation of the amyloid ␤ peptide (A␤) is proposed to play a key role in AD pathogenesis (2). A␤ is the post-proteolytic product of sequential cleavages of amyloid precursor protein by ␤-secretase and ␥-secretase. The commonly used 42-amino acid-long A␤ (A␤42) self-aggregates into oligomers, with larger aggregates forming A␤ plaques. However, soluble A␤ oligomers were proposed to be the cytotoxic form of the protein, acting extraor/and intracellularly (3).The severity of dementia and brain hypometabolism has been previously shown to be tightly linked (4), with brain hypometabolism preceding clinical signs of AD. This is directly associated with mitochondrial dysfunction being an early event in AD pathogenesis, as reflected in reduced metabolism, disruption of Ca 2ϩ homeostasis, increased free radical production, and lipid peroxidation (5-9). A␤ also affects mitochondrial respiration (10) and activates cytochrome c release, resulting in apoptosis (11). Importantly, A␤ does not cause toxicity in cells depleted of mitochondria (12). Finally, the mitochondrial protein, the voltage-dependent anion channel (VDAC), was shown to participate...

Voltage-Dependent Anion Channel 1 As an Emerging Drug Target for Novel Anti-Cancer Therapeutics

“…These include intracellular communication, as mediating calcium signal between the ER and mitochondria ( 41 ), being part of the outwardly rectifying depolarization-induced chloride (ORDIC) channel complex ( 42 ), regulate cell volume in brain ( 43 ), and mediate ATP release ( 44 ). Interestingly, silencing VDAC1 expression by specific small interfering RNA (siRNA) was shown to prevent the entry of amyloid beta (Aβ) into the cytosol, as well as Aβ-induced toxicity ( 45 ), suggesting the involvement of pl-VDAC1 in Aβ cell entry and in inducing mitochondrial dysfunction and apoptosis ( 46 ). These and other proposed functions for plVDAC were recently presented and discussed ( 31 ).…”

“…High-levels of VDAC1 were demonstrated in the dystrophic neurites of Aβ deposits in AD post-mortem brains and amyloid precursor protein transgenic mice ( 300 ). VDAC1 was shown to participate in Aβ-induced toxicity ( 45 , 301 , 302 ) where Aβ–VDAC1 interactions are toxic to AD-affected neurons ( 303 ) and VDAC1 interactions with Aβ and phosphorylated Tau lead to mitochondrial dysfunction ( 302 ). Recently ( 45 ), we demonstrated that Aβ interacts directly with VDAC1, specifically with the N-terminal region.…”

Novel insights into role of miR-320a-VDAC1 axis in astrocyte-mediated neuronal damage in neuroAIDS

“…In the present study, we investigated role of miR‐320a in regulating ATP release from astrocytes via the control of voltage dependent anion channel 1 (VDAC1) that culminates into astroglia‐induced neuronal death. VDAC1 has been implicated in various neurological disorders like Alzheimer's disease, Down Syndrome, Amyotrophic Lateral Sclerosis and Parkinson's Disease (Chu et al, ; Israelson et al, ; Smilansky et al, ; Yoo et al, ). VDAC1 is the most abundant outer membrane mitochondrial protein and provides major channel gateway for ATP release from mitochondria (Rostovtseva and Colombini, ).…”

Oligomerización Del Vdac-1: Apoptosis Mitocondrial

“…Esta interacción resulta en la formación de un hetero-oligomero de pl-VDAC-1-Aβ, permitiendo Aβ entrar a la célula. Aβ citosólico interactúa con VDAC-1 mitocondrial en el dominio N-Ter permitiendo su subsecuente oligomerización, y consecuente liberación de Citocromo c y finalmente muerte celular apoptótica (26).…”