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‘Protons to Patients: insights into lysosomal pH regulation from novel disease to lipid regulators’
Lysosomes are essential focal points of cellular metabolism, digesting a wide range of macromolecules provided by endocytosis or autophagy. To this end, lysosomes rely on their highly acidic luminal pH to promote the function of their many enzymes, a pH generated by the action of a v-Type proton pumping ATPase. Since this transporter is electrogenic, parallel ion movements must occur to dissipate the generated membrane potential and promote bulk proton flux. The Cl-/H+ antiporter, ClC-7, has been 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 patients with ClC-7 functional mutations have varying degrees of the same disease, with osteopetrosis sometimes associated with lysosomal storage disease.
I will discuss a novel disease manifested as widespread lysosomal dysfunction but no bone abnormalities, caused by a gain-of-function allele of ClC-7 that causes lysosomal hyperacidification, a highly unusual finding; our studies of the disease mechanism led to a novel treatment for the disease. I will also discuss new results demonstrating the regulation of ClC-7 by the lysosomal phosphoinositide, PI(3,5)P2. Inhibtion of PIKfyve, the enzyme which synthesizes PI(3,5)P2, also leads to lysosomal hyperacidification, 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 fundamental mechanisms of lysosomal pH regulation.
Date:
20 May 2024, 13:00
Venue:
Dorothy Crowfoot Hodgkin Building, off South Parks Road OX1 3QU
Venue Details:
Seminar Room 2, Room 20-138
Speaker:
Dr. Joseph Mindell (Senior Investigator, Membrane Transport Biophysics Section, NIH NINDS, USA)
Organising department:
Department of Biochemistry
Organiser:
Professor Simon Newstead (University of Oxford,)
Organiser contact email address:
simon.newstead@bioch.ox.ac.uk
Host:
Professor Simon Newstead (University of Oxford,)
Part of:
Biochemistry Department Seminar
Booking required?:
Not required
Audience:
Members of the University only
Editor:
Sarah-Jane Scard
