Oxidative stress and energy crises in neuronal dysfunction.
Mitochondrial dysfunction is implicated in many forms of cell death, particularly in the central nervous system. The mitochondria are required at the same time to generate adenosine 5'-triphosphate (ATP) for the cell, sequester excess cytoplasmic Ca(2+), and both produce and detoxify superoxide free radicals. The electron transport chain and proton circuit are central in keeping these three balls in the air at the same time. We have investigated the bioenergetics of the in situ mitochondria in cultured neurons exposed to pathological glutamate concentrations to model glutamate excitotoxicity and have revised the conventional view that mitochondrial calcium loading results in increased oxidative stress that damages the mitochondrion and ultimately the cell. Instead, a central role is played under these conditions by limitations in mitochondrial and cellular ATP generating capacity. Sodium and calcium entering via the N-methyl-D-aspartate receptor impose a large energetic load on cells and can use the entire respiratory capacity of the in situ mitochondria. As a result, even modest restrictions in mitochondrial capacity -- caused by low concentrations of electron transport chain inhibitors such as rotenone, as in models of Parkinson's disease; low concentrations of uncouplers, to test the so-called neuroprotective mild uncoupling hypothesis; or preexisting oxidative stress -- greatly potentiate glutamate excitotoxicity. Our findings may lead to a reevaluation of the potential for mild uncoupling to provide a neuroprotective role in aging-related neurodegenerative disorders because the deleterious consequences of restricting ATP generating capacity greatly outweigh the negligible effects on the levels of mitochondrial superoxide radicals in intact neurons.
Nicholls
David G
DG
Buck Institute for Age Research, Novato, CA 94945, USA. dnicholls@buckinstitute.org
D000255:Adenosine Triphosphate / Q000378:metabolism; D000375:Aging / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D004734:Energy Metabolism; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D009474:Neurons / Q000502:physiology*; D018384:Oxidative Stress
D000255:Adenosine Triphosphate; D002118:Calcium