Human Disease Model Report: mitochondrial disorders, VDAC-related

General Information

Name

mitochondrial disorders, VDAC-related

FlyBase ID

FBhh0000722

Disease Ontology Term

neurodegenerative disease

Parent Disease

OMIM

Overview

Although currently there are no human diseases associated with the mitochondrial voltage-dependent anion channel genes (VDAC1, VDAC2, VDAC3), phenotypes resulting from VDAC mutations in mouse have been described. VDACs appear to play a key role in the mitochondrial dysfunction observed for many neurodegenerative disorders, in particular, disorders associated with pathological protein aggregates. VDAC1 is the main mitochondrial docking site of many misfolded proteins, plays a key role in mitochondria-induced apoptosis, and also impacts calcium homeostasis within the cell.

There are 4 Drosophila genes orthologous to the 3 human VDAC genes. Dmel\porin exhibits the greatest homology to mammalian VDACs and is ubiquitously expressed; the other three Drosophila VDAC genes (Porin2, CG17139, and CG17140) have a more spatially restricted expression pattern, primarily in the male reproductive tract. Hypomorphic alleles resulting from imprecise excision of an insertion, RNAi targeting constructs, and alleles caused by insertional mutagenesis have been generated for Dmel\porin.

The human Hsap\VDAC1 gene has been introduced into flies, but has not been characterized in the context of this disease model.

Animals homozygous for severe loss-of-function alleles of Dmel\porin fail to survive to adulthood. Less severe alleles are semi-lethal; animals that survive to adulthood exhibit reduced lifespan, neurophysiology defects, locomotor defects, bang sensitivity, male sterility and female semi-sterility. A loss-of-function allele of porin was positive in a large-scale screen to identify mutations that result in retinal degeneration. Physical and genetic interactions of Dmel\porin have been described; see below and in the porin gene report.

See also the human disease model report 'calcium-induced neurotoxicity, TRP-channel-related' (FBhh0000723).

[updated Feb. 2018 by FlyBase; FBrf0222196]

Disease Summary Information

Disease Summary: mitochondrial disorders, VDAC-related

OMIM report

Human gene(s) implicated

Symptoms and phenotype

VDAC mutations in mouse exhibit an array of phenotypes, some of which are isoform-specific, including partial embryonic lethality, abnormal mitochondrial morphology in muscle, and infertility phenotypes (FBrf0210435 and references cited therein).

(FlyBase Curators, 2013-)

VDACs appear to play a key role in the mitochondrial dysfunction observed for many neurodegenerative disorders, in particular, disorders associated with pathological protein aggregates (Magri and Messian, 2017; pubmed:28571556).

(FlyBase Curators, 2013-)

Genetics

Cellular phenotype and pathology

Molecular information

Voltage-dependent anion channels (VDACs) are a family of small pore-forming proteins of the mitochondrial outer membrane found in all eukaryotes; three VDAC genes have been identified in mammals (FBrf0210435 and references cited therein).

(FlyBase Curators, 2013-)

The voltage-dependent anion channel (VDAC) lies in the outer mitochondrial membrane and forms a common pathway for the exchange of metabolites between the mitochondria and the cytosol, thus playing a crucial role in the regulation of metabolic and energetic functions of mitochondria. VDAC is also recognized to function in mitochondria-mediated apoptosis (Shoshan-Barmatz and Ben-Hail, 2012; pubmed:21530686).

(FlyBase Curators, 2013-)

VDAC1 is the main mitochondrial docking site of many misfolded proteins (Magri and Messian, 2017; pubmed:28571556).

(FlyBase Curators, 2013-)

VDAC dysfunction impacts calcium homeostasis within the cell (Shoshan-Barmatz, et al., 2018, pubmed:28712506).

(FlyBase Curators, 2013-)

External links

Gene2Function (human gene): VDAC1
Gene2Function (human gene): VDAC2
Gene2Function (human gene): VDAC3
Gene Cards: VDAC1
Gene Cards: VDAC2
Gene Cards: VDAC3
MedlinePlus (gene): VDAC1
MedlinePlus (gene): VDAC2
MedlinePlus (gene): VDAC3
MARRVEL (human gene): VDAC1
MARRVEL (human gene): VDAC2
MARRVEL (human gene): VDAC3
NCBI (Entrez) gene: VDAC1; voltage dependent anion channel 1
NCBI (Entrez) gene: VDAC2; voltage dependent anion channel 2
NCBI (Entrez) gene: VDAC3; voltage dependent anion channel 3

Disease synonyms

Related Diseases

Related human health report(s)

calcium-induced neurotoxicity, TRP-channel-related

Ortholog Information

Human gene(s) in FlyBase

Hsap\VDAC1

Human gene (HGNC)

Symbol / Name

VDAC3; voltage dependent anion channel 3

D. melanogaster ortholog (based on DIOPT)

Dmel\porin

(DIOPT, 2013-)

Comments on ortholog(s)

Many to many: 3 human to 4 Drosophila; the human genes are VDAC1, VDAC2, and VDAC3.

Human gene (HGNC)

Symbol / Name

VDAC1; voltage dependent anion channel 1

D. melanogaster ortholog (based on DIOPT)

Dmel\porin

(DIOPT, 2013-)

Comments on ortholog(s)

Many to many: 3 human to 4 Drosophila; the human genes are VDAC1, VDAC2, and VDAC3.

Human gene (HGNC)

Symbol / Name

VDAC2; voltage dependent anion channel 2

D. melanogaster ortholog (based on DIOPT)

Dmel\porin

(DIOPT, 2013-)

Comments on ortholog(s)

Many to many: 3 human to 4 Drosophila; the human genes are VDAC1, VDAC2, and VDAC3.

Other mammalian ortholog(s) used

D. melanogaster Gene Information (1)

Dmel\porin

Gene Snapshot

porin (porin) encodes a beta-barrel channel protein localized in the outer membrane of mitochondria that conducts translocation of various ions and metabolites between cytoplasm and mitochondria. It plays roles in mitochondria dynamics and mitophagy, and is ubiquitinated by the E3 ligases encoded by park and Mul1. [Date last reviewed: 2019-03-14]

Molecular function (GO)

voltage-gated monoatomic anion channel activity

Cellular component (GO)

Gene Groups / Pathways

VDAC
GLPSH

Comments on ortholog(s)

High-scoring ortholog of human VDAC1, VDAC2, and VDAC3; Dmel\porin shares 58-62% identity and 76-77% similarity with the human genes. There are three additional genes in this family in Drosophila: Porin2, CG17139, and CG17140; Dmel\porin is most closely related to the human genes.

Orthologs and Alignments from DRSC

DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans

H. sapiens (Human)

Other Genes Used: Viral, Bacterial, Synthetic (0)

Summary of Physical Interactions (71 groups)

porin

protein-protein

Interacting group

Assay

References

porin - AnxB10

experimental knowledge based

(Guruharsha et al., 2011)

porin - Arf1

experimental knowledge based

(Guruharsha et al., 2011)

porin - ATPsynB

experimental knowledge based

(Guruharsha et al., 2011)

porin - ATPsynβ

experimental knowledge based

(Guruharsha et al., 2011)

porin - ATPsynCF6

experimental knowledge based

(Guruharsha et al., 2011)

porin - ATPsynδ

experimental knowledge based

(Guruharsha et al., 2011)

porin - ATPsynF

experimental knowledge based

(Guruharsha et al., 2011)

porin - ATPsynγ

experimental knowledge based

(Guruharsha et al., 2011)

porin - ATPsynO

experimental knowledge based

(Guruharsha et al., 2011)

porin - blw

experimental knowledge based

(Guruharsha et al., 2011)

porin - CG2065

experimental knowledge based

(Guruharsha et al., 2011)

porin - CG2070

experimental knowledge based

(Guruharsha et al., 2011)

porin - CG3164

experimental knowledge based

(Guruharsha et al., 2011)

porin - CG7668

experimental knowledge based

(Guruharsha et al., 2011)

porin - CG13887

experimental knowledge based

(Guruharsha et al., 2011)

porin - CG15098

experimental knowledge based

(Guruharsha et al., 2011)

porin - CG33253

experimental knowledge based

(Guruharsha et al., 2011)

porin - Chd64

experimental knowledge based

(Guruharsha et al., 2011)

porin - Cisd

experimental knowledge based

(Guruharsha et al., 2011)

porin - clu

anti tag coimmunoprecipitation, western blot, anti bait coimmunoprecipitation, anti tag western blot, peptide massfingerprinting

(Sen et al., 2015)

porin - COX4

experimental knowledge based

(Guruharsha et al., 2011)

porin - Egfr

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

porin - Eno

experimental knowledge based

(Guruharsha et al., 2011)

porin - fax

experimental knowledge based

(Guruharsha et al., 2011)

porin - Fmr1

anti bait coimmunoprecipitation, western blot

(Geng et al., 2023)

porin - Gp93

experimental knowledge based

(Guruharsha et al., 2011)

porin - Gtpx

experimental knowledge based

(Guruharsha et al., 2011)

porin - Hsap\GSK3B

enzymatic study, luminiscence technology

(Yue et al., 2022)

porin - Hsp83

experimental knowledge based

(Guruharsha et al., 2011)

porin - Itpr

anti bait coimmunoprecipitation, western blot

(Lee et al., 2016)

porin - KdelR

experimental knowledge based

(Guruharsha et al., 2011)

porin - Kdsr

experimental knowledge based

(Guruharsha et al., 2011)

porin - Kr-h2

experimental knowledge based

(Guruharsha et al., 2011)

porin - Ldh

experimental knowledge based

(Guruharsha et al., 2011)

porin - Mcad

experimental knowledge based

(Guruharsha et al., 2011)

porin - Mec2

experimental knowledge based

(Guruharsha et al., 2011)

porin - Mf

experimental knowledge based

(Guruharsha et al., 2011)

porin - Miro

anti tag coimmunoprecipitation, western blot

(Lee et al., 2016)

porin - Mlc1

experimental knowledge based

(Guruharsha et al., 2011)

porin - Mlc2

experimental knowledge based

(Guruharsha et al., 2011)

porin - MRP

experimental knowledge based

(Guruharsha et al., 2011)

porin - Ost1

experimental knowledge based

(Guruharsha et al., 2011)

porin - Ost48

experimental knowledge based

(Guruharsha et al., 2011)

porin - OstΔ

experimental knowledge based

(Guruharsha et al., 2011)

porin - ox

experimental knowledge based

(Guruharsha et al., 2011)

porin - Pdi

experimental knowledge based

(Guruharsha et al., 2011)

porin - Phb1

experimental knowledge based

(Guruharsha et al., 2011)

porin - Phb2

experimental knowledge based

(Guruharsha et al., 2011)

porin - Pi3K21B

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

porin - Rab2

experimental knowledge based

(Guruharsha et al., 2011)

porin - Rab6

experimental knowledge based

(Guruharsha et al., 2011)

porin - Rap2l

experimental knowledge based

(Guruharsha et al., 2011)

porin - Rdh1

experimental knowledge based

(Guruharsha et al., 2011)

porin - regucalcin

experimental knowledge based

(Guruharsha et al., 2011)

porin - Rer1

experimental knowledge based

(Guruharsha et al., 2011)

porin - ScsβG

experimental knowledge based

(Guruharsha et al., 2011)

porin - SERCA

experimental knowledge based

(Guruharsha et al., 2011)

porin - sgg

proximity-dependent biotin identification, Identification by mass spectrometry

(Yue et al., 2022)

porin - spidey

experimental knowledge based

(Guruharsha et al., 2011)

porin - SsRβ

experimental knowledge based

(Guruharsha et al., 2011)

porin - Surf4

experimental knowledge based

(Guruharsha et al., 2011)

porin - Syb

experimental knowledge based

(Guruharsha et al., 2011)

porin - Tapδ

experimental knowledge based

(Guruharsha et al., 2011)

porin - Tecr

experimental knowledge based

(Guruharsha et al., 2011)

porin - Tm2

experimental knowledge based

(Guruharsha et al., 2011)

porin - Tspo

experimental knowledge based

(Guruharsha et al., 2011)

porin - up

experimental knowledge based

(Guruharsha et al., 2011)

porin - UQCR-C2

experimental knowledge based

(Guruharsha et al., 2011)

porin - Vha68-2

experimental knowledge based

(Guruharsha et al., 2011)

porin - wal

experimental knowledge based

(Guruharsha et al., 2011)

porin - ZnT63C

experimental knowledge based

(Guruharsha et al., 2011)

Alleles Reported to Model Human Disease (Disease Ontology) (4 alleles)

porin

Models Based on Experimental Evidence ( 3 )

Allele

Disease

Evidence

References

porin^k05123

model of retinal degeneration

CEA

(Huang et al., 2015)

model of Huntington's disease

CEC with Hsap\HTT^Q93.ex1.UAS

(Khalil et al., 2015)

porin^KK107645

model of neurodegenerative disease

CEA

(M'Angale and Staveley, 2016)

porin^JF03251

model of neurodegenerative disease

CEA

(M'Angale and Staveley, 2016)

Modifiers Based on Experimental Evidence ( 4 )

Allele

Disease

Interaction

References

porin^f03616

ameliorates Huntington's disease

modeled by Hsap\HTT^{128Q.1-336.UAS}

(Kaltenbach et al., 2007)

porin^k05123

ameliorates Huntington's disease

modeled by Hsap\HTT^{128Q.1-336.UAS}

(Al-Ramahi et al., 2018, Kaltenbach et al., 2007)

porin^KK107645

exacerbates Parkinson's disease 1

modeled by Hsap\SNCA^UAS.cFa

(M'Angale and Staveley, 2016)

porin^JF03251

ameliorates Parkinson's disease 6

modeled by Pink1^B9

(Lee et al., 2018)

ameliorates Parkinson's disease

modeled by Miro^UAS.Tag:MYC

(Lee et al., 2018)

ameliorates neurodegenerative disease

modeled by par-1^UAS.cUa

(Lee et al., 2018)

model of neurodegenerative disease

is ameliorated by Buffy^UAS.cQa

(M'Angale and Staveley, 2016)

exacerbates Parkinson's disease 1

modeled by Hsap\SNCA^UAS.cFa

(M'Angale and Staveley, 2016)

Alleles Representing Disease-Implicated Variants

Genetic Tools, Stocks and Reagents

Sources of Stocks

Contact lab of origin for a reagent not available from a public stock center.

Bloomington Stock Center Disease Page

Related mammalian, viral, bacterial, or synthetic transgenes

Allele

Transgene

Publicly Available Stocks

Hsap\VDAC1^{UAS.cBa.Tag:HA}

PBac{UAS-hVDAC1.HA.B}

y¹ w^*; PBac{UAS-hVDAC1.HA.B}VK00033

Hsap\VDAC1^UAS.cZa

P{UAS-hVDAC1.Z}

w^*; P{UAS-hVDAC1.Z}attP40

Hsap\VDAC1^UAS.Tag:HA

P{UAS-hVDAC1.HA}

w^*; P{UAS-hVDAC1.HA}attP40

Selected Drosophila transgenes

Allele

Transgene

Publicly Available Stocks

RNAi constructs available

Allele

Transgene

Publicly Available Stocks

y¹ v¹; P{TRiP.JF03251}attP2/TM3, Sb¹

porin^RNAi.Sym.UAS

P{UAS-porin.RNAi.Sym}

y¹ sc^* v¹ sev²¹; P{TRiP.HMS05687}attP40

Selected Drosophila classical alleles

Allele

Allele class

Mutagen

Publicly Available Stocks

porin^k05123

P-element activity

y^d2 w¹¹¹⁸ P{ey-FLP.N}2 P{5xglBS-lacZ.38-1}TPN1; P{lacW}porin^k05123 P{neoFRT}40A/CyO y⁺

porin^f03616

piggyBac activity

w¹¹¹⁸; PBac{WH}porin^f03616

References (8)

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