DISRUPTION OF MITOCHONDRIAL RESPIRATION INHIBITS VOLUME-REGULATED ANION CHANNELS AND PROVOKES NEURONAL CELL SWELLING

Hypoxia and inhibitors of mitochondrial respiration impair the regulat ory volume decrease (RVD) of cerebellar granule neurons after hypotoni c swelling. RVD is linked to the opening of volume-regulated anion cha nnels (VRACs). VRACs are outwardly rectifying, inactivate slowly durin g maintained depolarization,land are permeable to the cellular organic osmolyte taurine. Channel activation requires nonhydrolytic ATP bindi ng and is not modulated by intracellular ADP. VRAC opening is reversib ly depressed by hypoxia and by mitochondrial inhibitors such as oligom ycin, rotenone, and antimycin A. These results demonstrate that neuron al VRAC activation and swelling are both tightly linked to cellular en ergy. Moreover, the findings reported in this work may have a particul ar significance for inherited mitochondrial human diseases, such as mi tochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), which cause brain swelling and edema.