Mitochondrial ATP-Mg/Pi Carrier SCaMC-3/Slc25a23 Counteracts PARP-1-dependent Fall in Mitochondrial ATP Caused by Excitotoxic Insults in Neurons

Overview

Journal J Neurosci

Specialty Neurology

Date 2015 Feb 27

PMID 25716855

Citations 24

Authors

Carlos B Rueda

Javier Traba

Ignacio Amigo

Irene Llorente-Folch

Paloma Gonzalez-Sanchez

Beatriz Pardo

Jose A Esteban

Araceli Del Arco

Jorgina Satrustegui

Affiliations

Soon will be listed here.

Abstract

Glutamate excitotoxicity is caused by sustained activation of neuronal NMDA receptors causing a large Ca(2+) and Na(+) influx, activation of poly(ADP ribose) polymerase-1 (PARP-1), and delayed Ca(2+) deregulation. Mitochondria undergo early changes in membrane potential during excitotoxicity, but their precise role in these events is still controversial. Using primary cortical neurons derived from mice, we show that NMDA exposure results in a rapid fall in mitochondrial ATP in neurons deficient in SCaMC-3/Slc25a23, a Ca(2+)-regulated mitochondrial ATP-Mg/Pi carrier. This fall is associated with blunted increases in respiration and a delayed decrease in cytosolic ATP levels, which are prevented by PARP-1 inhibitors or by SCaMC-3 activity promoting adenine nucleotide uptake into mitochondria. SCaMC-3 KO neurons show an earlier delayed Ca(2+) deregulation, and SCaMC-3-deficient mitochondria incubated with ADP or ATP-Mg had reduced Ca(2+) retention capacity, suggesting a failure to maintain matrix adenine nucleotides as a cause for premature delayed Ca(2+) deregulation. SCaMC-3 KO neurons have higher vulnerability to in vitro excitotoxicity, and SCaMC-3 KO mice are more susceptible to kainate-induced seizures, showing that early PARP-1-dependent fall in mitochondrial ATP levels, counteracted by SCaMC-3, is an early step in the excitotoxic cascade.

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