Disruption of mitochondrial respiration inhibits volume-regulated anion channels and provokes neuronal cell swelling.
Hypoxia and inhibitors of mitochondrial respiration impair the regulatory volume decrease (RVD) of cerebellar granule neurons after hypotonic swelling. RVD is linked to the opening of volume-regulated anion channels (VRACs). VRACs are outwardly rectifying, inactivate slowly during maintained depolarization, and are permeable to the cellular organic osmolyte taurine. Channel activation requires nonhydrolytic ATP binding and is not modulated by intracellular ADP. VRAC opening is reversibly depressed by hypoxia and by mitochondrial inhibitors such as oligomycin, rotenone, and antimycin A. These results demonstrate that neuronal VRAC activation and swelling are both tightly linked to cellular energy. Moreover, the findings reported in this work may have a particular significance for inherited mitochondrial human diseases, such as mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), which cause brain swelling and edema.
Patel
A J
AJ
Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, UPR 411, 06560 Valbonne, France.
Lauritzen
I
I
Lazdunski
M
M
Honoré
E
E
D000818:Animals; D000838:Anions; D015687:Cell Hypoxia / Q000502:physiology*; D019069:Cell Respiration / Q000502:physiology*; D048429:Cell Size / Q000502:physiology; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000502:physiology*; D018118:Chloride Channels / Q000502:physiology*; D006801:Humans; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000502:physiology*; D009474:Neurons / Q000502:physiology* / Q000648:ultrastructure; D018408:Patch-Clamp Techniques; D014981:Xenopus
D000838:Anions; D018118:Chloride Channels