Table Of ContentStine Helene Falsig Pedersen
Diane L. Barber Editors
Organelles
in Disease
185
Reviews of Physiology, Biochemistry and
Pharmacology
Volume 185
Editor-in-Chief
StineHelene FalsigPedersen,DepartmentofBiology,UniversityofCopenhagen,
Copenhagen,Denmark
SeriesEditors
DianeL.Barber,DepartmentofCellandTissueBiology,UniversityofCalifornia
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EmmanuelleCordat,DepartmentofPhysiology,UniversityofAlberta,Edmonton,
Canada
MayumiKajimura,DepartmentofBiochemistry,KeioUniversity,Tokyo,Japan
JensG.Leipziger,DepartmentofBiomedicine,AarhusUniversity,Aarhus,Denmark
MarthaE.O’Donnell,DepartmentofPhysiologyandMembraneBiology,Univer-
sityofCaliforniaDavisSchoolofMedicine,Davis,USA
LuisA.Pardo,MaxPlanckInstituteforExperimentalMedicine,G€ottingen,Germany
Nicole Schmitt, Department of Biomedical Sciences, University of Copenhagen,
Copenhagen,Denmark
ChristianStock,DepartmentofGastroenterology,HannoverMedicalSchool,Han-
nover,Germany
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Stine Helene Falsig Pedersen Diane L. Barber
Editors
Organelles in Disease
Editors
StineHeleneFalsigPedersen DianeL.Barber
DepartmentofBiology SchoolofDentistry,DepartmentofCell
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Acknowledgements
Contributionstothisvolumehavepartlybeenpersonallyinvited,withkindsupport
of the series editors D.L. Barber, E. Cordat, M. Kajimura, J.G. Leipziger, M.E.
O’Donnell,L.A.Pardo,N.Schmitt,andC.Stock
v
Contents
GolgipHandIonHomeostasisinHealthandDisease. . . . . . . . . . . . . . 1
ElhamKhosrowabadiandSakariKellokumpu
StressGranulesinCancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
Min-SeokSongandEldaGrabocka
LipidDropletsinCancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
ToniPetan
PatternsofCiliationandCiliarySignalinginCancer. . . . . . . . . . . . . . 87
AnnaA.Kiseleva,AnnaS.Nikonova,andEricaA.Golemis
TargetingCancerLysosomeswithGoodOldCationicAmphiphilic
Drugs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
Anne-MarieEllegaard,PeterBach,andMarjaJa¨a¨ttela¨
Cancer-RelatedIncreasesandDecreasesinCalciumSignaling
attheEndoplasmicReticulum-MitochondriaInterface(MAMs). . . . . . 153
AlbertoDanese,SaverioMarchi,VeronicaAngelaMariaVitto,
LorenzoModesti,SaraLeo,MariuszR.Wieckowski,CarlottaGiorgi,
andPaoloPinton
EndosomalAcid-BaseHomeostasisinNeurodegenerativeDiseases. . . . 195
HariPrasadandRajiniRao
EndolysosomalDisordersAffectingtheProximalTubuleoftheKidney:
NewMechanisticInsightsandTherapeutics. .. . . . . . . . .. . . . . . . . .. . 233
BeatricePaolaFesta,MarineBerquez,DanielaNieri,
andAlessandroLuciani
Endo-LysosomalCationChannelsandInfectiousDiseases. . . . . . . . . . . 259
Yu-KaiChao,Sui-YuanChang,andChristianGrimm
vii
RevPhysiolBiochemPharmacol(2023)185:1–24
https://doi.org/10.1007/112_2020_49
©TheAuthor(s),underexclusivelicensetoSpringer
NatureSwitzerlandAG2020
Publishedonline:2September2020
Golgi pH and Ion Homeostasis in Health
and Disease
ElhamKhosrowabadiandSakariKellokumpu
Contents
1 Introduction................................................................................... 2
2 MaintenanceofGolgipHHomeostasis...................................................... 2
2.1 GolgiAcidificationbytheV-ATPase................................................. 3
2.2 CounterIonTransport.................................................................. 3
2.3 ProtonLeakagePathway............................................................... 5
2.4 GolgiHomeostasisofOtherIons...................................................... 7
3 DiseasesAssociatedwithAlteredGolgipHandIonHomeostasis.......................... 8
3.1 AutosomalRecessiveCutisLaxaTypeII............................................. 8
3.2 Cancers................................................................................. 9
3.3 ViralInfections......................................................................... 10
3.4 MultigenerationalNon-syndromicIntellectualDisability(ID)........................ 11
3.5 AngelmanSyndromeandAutismSpectrumDisorders............................... 12
3.6 Hailey-HaileyDisease.................................................................. 13
3.7 CongenitalDisorderofGlycosylation2K(CDG2K).................................. 13
3.8 MenkesDiseaseandRelatedSyndromes.............................................. 14
4 PerspectivesandKeyQuestions.............................................................. 14
References......................................................................................... 17
Abstract Maintenance of the main Golgi functions, glycosylation and sorting, is
dependentontheuniqueGolgipHmicroenvironmentthatisthoughttobesetbythe
balance between the rates of V-ATPase-mediated proton pumping and its leakage
back to the cytoplasm via an unknown pathway. The concentration of other ions,
suchaschloride,potassium,calcium,magnesium,andmanganese,isalsoimportant
for Golgi homeostasis and dependent on the transport activity of other ion trans-
porters present in the Golgi membranes. During the last decade, several new
Author Contributions: E. Khosrowabadi and S. Kellokumpu both participated in writing and
reviewingofthefinalmanuscript.E.Khosrowabadimadethefiguresandeditedthe
referencesandthetext;S.Kellokumpumadefinalrevisionstothetext.
E.KhosrowabadiandS.Kellokumpu(*)
FacultyofBiochemistryandMolecularMedicine,UniversityofOulu,Oulu,Finland
e-mail:elham.khosrowabadi@oulu.fi;sakari.kellokumpu@oulu.fi
2 E.KhosrowabadiandS.Kellokumpu
disorders have been identified that are caused by, or are associated with,
dysregulated Golgi pH and ion homeostasis. Here, we will provide an updated
overview on these disorders and the proteins involved. We will also discuss other
disorders for which the molecular defects remain currently uncertain but which
potentiallyinvolveproteinsthatregulateGolgipHorionhomeostasis.
Keywords Disease·Golgidysfunction·Golgihomeostasis·Ionbalance·Resting
pH
1 Introduction
ThepHofsecretoryandendocyticcompartmentsisknowntobeuniquelyacidicin
each compartment and crucial for their efficient functioning in mammalian cells
(Kim et al. 1996; Demaurex et al. 1998; Palokangas et al. 1998; Schapiro and
Grinstein 2000; Wu et al. 2001; Paroutis et al. 2004, for a recent review, see also
Kellokumpu 2019).Ingeneral,theacidityofthesecretory compartments increases
toward the plasma membrane, while the pH of endosomal compartments increases
toward the cell center (late endosomes and lysosomes). Among all these compart-
ments,theGolgiapparatusisthemostenigmaticone,asitrepresentsaconverging
pointbetweenthetwopathways,receivingvesicularcarriersfromtheendoplasmic
reticulum(neutral)andtheendosomalcompartments(acidic)andsendingthemback
to these destinations as part of its sorting functions. Moreover, Golgi resting pH
decreasesfromthecis-Golgicisternae (pH6.7)tomedial(pH6.5)andtrans-Golgi
cisternae (pH 6.3) reaching pH 6.0 at the TGN. How this pH gradient along the
cis-trans axis of Golgi cisternae is established is not completely clear, but it may
involvetwodifferentmechanisms,whichbeneednotbemutuallyexclusive:thefirst
onemayinvolveselectivetraffickingofvesicularcarriersbetweenthecis-Golgiand
theneutralERandbetweenthetrans-Golgiandtheacidicendosomalcompartments.
The other one is the number of proton pumps or proton leak “channels” that may
change along the cis-trans axis of the Golgi stack (Wu et al. 2001; Paroutis et al.
2004).
2 Maintenance of Golgi pH Homeostasis
The resting pH of the Golgi lumen is known to be established and maintained by
threemainiontransportsystemsthatincludethevacuolar(V)-ATPase,acounterion
(Cl(cid:1) or K+) transport, and a proton “leak” pathway that shuttles protons from the
Golgilumenbacktothecytoplasm(Wuetal.2001;Demaurex2002;Paroutisetal.
2004).Eachofthesethreesystemsisbrieflydiscussedbelow.
GolgipHandIonHomeostasisinHealthandDisease 3
2.1 Golgi Acidification by the V-ATPase
TheV-ATPaseisthemainacidifierofallsecretoryandendocyticcompartments.Itis
a multimeric protein complex whose oligomeric structure varies between different
compartments.Consistentwiththis,uniquesubunitisoformsarefoundinmammals,
theexpressionofwhichisoftentissue-andcelltype-specific(MarshanskyandFutai
2008). For example, multiple isoforms are found for the a-subunit which seems to
dictatetheV-ATPasesintodistinctintracellularlocalizations.InyeasttheN-terminal
cytosolicdomainsoftwoa-subunitisoforms(Vph1pandStv1p)areresponsiblefor
the specific targeting of V-ATPase to vacuolar and Golgi compartments, respec-
tively. In mice and humans, there are four distinct a-subunit isoforms (a1-a4) of
whichthea2-subunitseemstodictatethelocalizationoftheV-ATPaseintheGolgi
membranes.TheotherisoformsarefoundinV-ATPasesthatareexpressedvariably
at the plasma membrane and/or endosomal-lysosomal compartments (Marshansky
andFutai2008;Flincketal.2020).
The V-ATPase uses ATP as an energy source to pump protons into the Golgi
lumen(Fig.1top).Itsactivityisthereforedependentoncellularglucoseornutrient
levels.Undernormalconditions,itisassumedtobeconstantlyactive(Schapiroand
Grinstein 2000; Wu et al. 2001). Consistent with this view, addition of excess
(10 mM) ATP induces rapid Golgi acidification that equilibrates after few minutes
atpH~5(Fig.1top),i.e.,lowerthanthenormalrestingpH.Thisprobablyreflects
experimental setup (high potassium bath solution without buffering, excess ATP).
Likewise,Golgilumenstartstoalkalinizewithinfewsecondsequilibratingatneutral
pH within few minutes after blocking the V-ATPase activity by using its specific
inhibitorconcanamycinA(Fig.1,bottom).
2.2 Counter Ion Transport
ContinuousprotonpumpingbytheV-ATPasehasthepropensitytoincreaseGolgi
membranepotential(insidepositive)thatthenwouldslowdowntheactivityofthe
V-ATPaseandthusGolgiacidity.Therefore,tokeepmembranepotentialunaltered,
proton pumping needs to be counteracted by Cl(cid:1) import or K+ (Glickman et al.
1983;SchapiroandGrinstein2000;Paroutisetal.2004).Instrongsupportofthis,
(cid:1)
protein termed the GPHR (Golgi pH regulator), a Cl channel, was shown to be
necessary for the maintenance of sufficiently acidic Golgi resting pH in the cells
(Maedaetal.2008).Inaddition,itsmutagenesiswasshowntoalterglycosylation,to
delayproteintransporttotheplasmamembrane,andtoinduceGolgifragmentation.
OtherstudieshavesuggestedthatpassiveK+efflux(insteadofCl(cid:1)influx)isused
to counteract membrane potential increase brought about by proton pumping
(Howell and Palade 1982). This may relate to the high permeability of the Golgi
membranes to K+ ions (Schapiroand Grinstein 2000) which could be mediated by
Na+andK+conductivechannelssuchastheKv1.3(Zhuetal.2014)inconjunction
