We investigate the molecular pathomechanisms of disease-causing mutations in the mitochondrial alpha-keto acid dehydrogenase complexes. The respective enzyme deficiencies primarily hit the neuronal cells, of high energy demand, and operation of the nervous system due to the central roles of these complexes in aerobic metabolism. These complexes not only play crucial roles in cellular bioenergetics (ATP production), but also contribute to reactive oxygen species (ROS) generation; pathological increase in ROS has great significance in neuronal disorders (like stroke, neurodegenerative diseases, etc.). Although the physiological mechanisms are analogous for all of these complexes, the clinical manifestations of their respective deficiencies show a broad spectrum. The E3 subunit is common to all the cognate complexes, hence its compromised activity affects several central metabolic pathways simultaneously and generally leads to the most severe clinical consequences, including premature death. Important auxiliary elements in the molecular pathologies are enhanced ROS generation and compromised subunit interactions. To address these complex pathomechanisms, we attempt to: i. structurally and functionally characterize the wild-type and disease-causing mutant complexes, ii. investigate the ROS generation by the complexes and their disease-causing variants, and iii., explore the effects of the deficiencies on cellular bioenergetics.