Chemical Biology: Approaches to Drug Discovery and Development to Targeting Disease

Chapter 22: Mitochondrial Medicine

Richard J. T. Rodenburg

Jan A. M. Smeitink

Radboud University Nijmegen Medical Centre, Nijmegen Center for Mitochondrial Disorders, The Netherlands

Mitochondrial medicine is an emerging field in medicine that focuses on diseases in which the mitochondrial energy generating system plays a central role. These diseases include the “classical” mitochondrial disorders, in which a (genetic) defect in the mitochondrial energy generating system is the primary cause of the disease, but also more common disorders such as Parkinson and cancer, in which mitochondrial energy metabolism plays an important role in the pathogenesis. In this review, we present an overview of the mitochondrial energy generating system, starting at the conversion of pyruvate into acetyl-CoA by pyruvate dehydrogenase, via the TCA cycle in which reduction equivalents are formed, to the oxidative phosphorylation system, where the reduction equivalents are used to convert ADP into ATP. The mitochondrial energy generating system can be examined by global assays that measure the rate of pyruvate conversion, the rate of oxygen consumption, or the rate of ATP production. In addition, an overview is given of the spectrophotometric assays that are available to measure PDHc, several TCA cycle enzymes, and the enzymes of the oxidative phosphorylation. In the diagnostic analysis of patients suspected to suffer from a mitochondrial disorder, these assays are applied to evaluate the functioning ...