The Cl-/H+ antiporter ClC-7 is the primary chloride permeation pathway in lysosomes
Abstract
Lysosomes are the stomachs of the cell-terminal organelles on the endocytic pathway where internalized macromolecules are degraded. Containing a wide range of hydrolytic enzymes, lysosomes depend on maintaining acidic luminal pH values for efficient function. Although acidification is mediated by a V-type proton ATPase, a parallel anion pathway is essential to allow bulk proton transport. The molecular identity of this anion transporter remains unknown. Recent results of knockout experiments raise the possibility that ClC-7, a member of the CLC family of anion channels and transporters, is a contributor to this pathway in an osteoclast lysosome-like compartment, with loss of ClC-7 function causing osteopetrosis. Several mammalian members of the CLC family have been characterized in detail; some (including ClC-0, ClC-1 and ClC-2) function as Cl--conducting ion channels, whereas others act as Cl-/H+antiporters (ClC-4 and ClC-5). However, previous attempts at heterologous expression of ClC-7 have failed to yield evidence of functional protein, so it is unclear whether ClC-7 has an important function in lysosomal biology, and also whether this protein functions as a Cl- channel, a Cl-/H+ antiporter, or as something else entirely. Here we directly demonstrate an anion transport pathway in lysosomes that has the defining characteristics of a CLC Cl-/H+ antiporter and show that this transporter is the predominant route for Cl- through the lysosomal membrane. Furthermore, knockdown of ClC-7 expression by short interfering RNA can essentially ablate this lysosomal Cl-/H+ antiport activity and can strongly diminish the ability of lysosomes to acidify in vivo, demonstrating that ClC-7 is a Cl-/H+ antiporter, that it constitutes the major Cl- permeability of lysosomes, and that it is important in lysosomal acidification.
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In the ruffled border, V-ATPase helps to acidify the resorption lacuna and enable dissolution of hydroxyapatite crystals.
“In the ruffled border, there is a vacuolar-type H+-ATPase (V-ATPase), which helps to acidify the resorption lacuna and hence to enable dissolution of hydroxyapatite crystals [20, 100, 101].”
From Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells (2015) · cites this paper as [101]
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- Authors
- Graves, A. R., Curran, P. K., Smith, C. L., & Mindell, J. A.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Mindell, Joseph A.
- Venue
- Nature
- Published
- 2008-04-30
- Volume
- 453
- Issue
- 7196
- Pages
- 788-792
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2090977690
- Cited by
- 399
- References
- 23
- Citations by year
- 2026: 17 · 2025: 20 · 2024: 18 · 2023: 27 · 2022: 23 · 2021: 24 · 2020: 22 · 2019: 18 · 2018: 18 · 2017: 17 · 2016: 15 · 2015: 20 · 2014: 21 · 2013: 21 · 2012: 18
- FWCI
- 13.56
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- ClC-7, lysosomal membrane, chloride permeation, lysosomal acidification, membrane potential, CLC family, anion transport, osteopetrosis, osteoclasts, V-type proton ATPase, heterologous expression, osteoclast-like cells
- MeSH terms
- Animals, Chlorides, Fluorescence, HeLa Cells, Humans, Hydrogen-Ion Concentration, Liver, Lysosomes, Permeability, Protons, Ion Transport, Antiporters, Chloride Channels, Rats
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