The role of the mitochondrion in neurodegeneration is a paradox. On the one hand, vital mitochondrial tasks, such as energy production and calcium buffering, provide an important foundation for all neuronal functions. Yet, on the other, mitochondrial free radical production and involvement in cell-death cascades may lead to a neuron's untimely demise.
It is now clear that mitochondria are not merely neuronal “power plants”, but are highly complex, integrated organelles whose function transcends that of simple energy production. In addition to providing the majority of neuronal energy via oxidative phosphorylation, mitochondria play a central role in intracellular ion homeostasis, free radical management, and gene and protein expression.
This chapter will focus on the biology of mitochondrial electron transport, oxidative phosphorylation and other mitochondrial functions, and will discuss the effects of mitochondrial toxins on mitochondrial function and neuronal viability. It will explore briefly one of the main consequences of oxidative metabolism, mitochondrial free radical production and how this and other mitochondrial factors potentially contribute to neuronal death.
Mitochondrial energy production and sites of action for metabolic inhibitors
Mitochondria efficiently convert the potential energy of glucose into a usable cellular energy currency, primarily ATP. Glucose is the primary basis for neuronal energy metabolism; ketone bodies can provide a limited energy source, but only in situations of chronic metabolic imbalance.
Glucose crosses the blood–brain barrier in an insulin-independent manner and is taken up by membrane transporters. It is phosphorylated almost immediately by hexokinase and enters glycolysis.