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SUMMARY:‘Protons to Patients: insights into lysosomal pH regulation from
  novel disease to lipid regulators’ - Dr. Joseph Mindell (Senior Investi
 gator\, Membrane Transport Biophysics Section\, NIH NINDS\, USA)
DTSTART;VALUE=DATE-TIME:20240520T130000
DTEND;VALUE=DATE-TIME:20240520T140000
UID:https://talks.ox.ac.uk/talks/id/7a3a0f9d-b61b-4058-b0d6-1af453c25930/
DESCRIPTION:Lysosomes are essential focal points of cellular metabolism\, 
 digesting a wide range of macromolecules provided by endocytosis or autoph
 agy. To this end\, lysosomes rely on their highly acidic luminal pH to pro
 mote the function of their many enzymes\, a pH generated by the action of 
 a v-Type proton pumping ATPase. Since this transporter is electrogenic\, p
 arallel ion movements must occur to dissipate the generated membrane poten
 tial and promote bulk proton flux. The Cl-/H+ antiporter\, ClC-7\, has bee
 n proposed to play this role\, moving Cl- in parallel to protons. However\
 , the function of ClC-7 has been controversial\, with conflicting reports 
 on its contribution to lysosomal acidification. All heretofore known patie
 nts with ClC-7 functional mutations have varying degrees of the same disea
 se\, with osteopetrosis sometimes associated with lysosomal storage diseas
 e. \n\nI will discuss a novel disease manifested as widespread lysosomal d
 ysfunction but no bone abnormalities\, caused by a gain-of-function allele
  of ClC-7 that causes lysosomal hyperacidification\, a highly unusual find
 ing\; our studies of the disease mechanism led to a novel treatment for th
 e disease. I will also discuss new results demonstrating the regulation of
  ClC-7 by the lysosomal phosphoinositide\, PI(3\,5)P2. Inhibtion of PIKfyv
 e\, the enzyme which synthesizes PI(3\,5)P2\, also leads to lysosomal hype
 racidification\, through a largely ClC-7-dependent mechanism. Finally\, I 
 will discuss recent experiment demonstrating that these two phenomena are 
 deeply related to each other through effects on the ClC-7 gating mechanism
 . These findings strengthen the evidence for an important role of ClC-7 in
  the lysosomal acidification process and yield insights into the fundament
 al mechanisms of lysosomal pH regulation.\n\nSpeakers:\nDr. Joseph Mindell
  (Senior Investigator\, Membrane Transport Biophysics Section\, NIH NINDS\
 , USA)
LOCATION:Dorothy Crowfoot Hodgkin Building (Seminar Room 2\, Room 20-138)\
 , off South Parks Road OX1 3QU
TZID:Europe/London
URL:https://talks.ox.ac.uk/talks/id/7a3a0f9d-b61b-4058-b0d6-1af453c25930/
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DESCRIPTION:Talk:‘Protons to Patients: insights into lysosomal pH regula
 tion from novel disease to lipid regulators’ - Dr. Joseph Mindell (Senio
 r Investigator\, Membrane Transport Biophysics Section\, NIH NINDS\, USA)
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