Because of their high-energy metabolism, neurons are strictly dependent on mitochondria, which generate cellular ATP through oxidative phosphorylation. The mitochondrial genome encodes for critical components of the oxidative phosphorylation pathway machinery, and therefore, mutations in mitochondrial DNA (mtDNA) cause energy production defects that frequently have severe neurological manifestations. Here, we review the principles of mitochondrial genetics and focus on prototypical mitochondrial diseases to illustrate how primary defects in mtDNA or secondary defects in mtDNA due to nuclear genome mutations can cause prominent neurological and multisystem features. In addition, we discuss the pathophysiological mechanisms underlying mitochondrial diseases, the cellular mechanisms that protect mitochondrial integrity, and the prospects for therapy. The nervous system relies on mitochondrial metabolism to drive energy-consuming processes. Carelli and Chan illustrate how defects in mitochondrial DNA lead to neurological dysfunction and discuss how research in mitochondrial biology can unravel pathogenic mechanisms and translate into therapy.
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