Neurodegeneration in primary mitochondrial disorders

Abstract

Mitochondria are critically responsible for the generation of energy in the form of ATP through the electron transport chain (ETC). The central nervous system (CNS) performs highly energy-intensive tasks and is therefore particularly dependent on ATP. Defects residing within the complexes comprising the ETC can affect the synthesis of ATP and consequently severely compromise neuronal function. It is unsurprising then that primary mitochondrial DNA mutations are an important cause of neurological disease. The clinical presentation is often heterogeneous in terms of age of onset and different neurological signs and symptoms which might include ataxia, seizures, cognitive decline, blindness, and stroke. The clinical course can vary considerably but in many patients there is progressive neurological decline and marked neurodegeneration. Our understanding of the mechanisms underpinning neurodegenerative changes due to mitochondrial DNA mutations is limited due to the availability of appropriate animal models of disease. However, studies on human postmortem CNS tissues have provided an invaluable insight into the distribution and severity of neuronal degeneration in patients harboring mitochondrial DNA defects. In this chapter, we describe the neuropathological changes occurring in the CNS associated with different mutations of the mitochondrial genome and discuss the mechanisms which might contribute to neural dysfunction and cell death.