Mitochondrial dysfunction can connect the diverse medical symptoms associated with autism spectrum disorders

Abstract

Autism spectrum disorder (ASD) is a devastating neurodevelopmental disorder. Over the past decade, evidence has emerged that some children with ASD suffer from undiagnosed comorbid medical conditions. One of the medical disorders that has been consistently associated with ASD is mitochondrial dysfunction. Individuals with mitochondrial disorders without concomitant ASD manifest dysfunction in multiple high-energy organ systems, such as the central nervous, muscular, and gastrointestinal (GI) systems. Interestingly, these are the identical organ systems affected in a significant number of children with ASD. This finding increases the possibility that mitochondrial dysfunction may be one of the keys that explains the many diverse symptoms observed in some children with ASD. This article will review the importance of mitochondria in human health and disease, the evidence for mitochondrial dysfunction in ASD, the potential role of mitochondrial dysfunction in the comorbid medical conditions associated with ASD, and how mitochondrial dysfunction can bridge the gap for understanding how these seemingly disparate medical conditions are related. We also review the limitations of this evidence and other possible explanations for these findings. This new understanding of ASD should provide researchers a pathway for understanding the etiopathogenesis of ASD and clinicians the potential to develop medical therapies.

Figure 1

Mitochondrial function, features associated with mitochondrial disease and the features and consequences of mitochondrial dysfunction in autism spectrum disorder (ASD). The top panel outlines some of the features and metabolic markers used to diagnose mitochondrial disease. The features are divided up into those that are not typically clinically abnormal in ASD and those found to be clinically abnormal in some individuals with ASD. Features in which the association with ASD is unclear are not listed in this panel. The mitochondrion is represented diagrammatically in the middle of the figure. Glucose and fatty acids are processed through separate but overlapping pathways to create adenosine triphosphate (ATP). The fatty acid oxidation pathway, tricarboxylic acid (TCA) cycle and the pyruvate dehydrogenase complex are located within the mitochondrion matrix which is located inside the inner mitochondrial membrane. Long chain fatty acids require the carnitine shuttle to enter the mitochondrial matrix while medium and short chain fatty acids do not require the carnitine shuttle. One of the enzymes for the TCA cycle, succinate dehydrogenase, is complex II of the electron transport chain (ETC). Electron carriers, NADH and FADH₂, transfer energy from the TCA cycle and fatty acid oxidation pathway to the ETC. The ETC is the final common pathway for the generation of ATP from adenosine diphosphate (ADP). The bottom panel lists some of the physiological consequences of mitochondrial dysfunction.