Genetic Dissection of Energy-Deficiency in Autism Spectrum Disorder

An important new consideration of Autism Spectrum Disorder (ASD) is the bioenergetic mechanisms underlying the recent rapid evolutionary expansion of the human brain, and the fundamental risks this poses for mitochondrial dysfunction and calcium signaling abnormalities, and their potential role in ASD with insights from the BTBR mouse model of ASD. The rapid brain expansion in Homo sapiens, particularly in the parietal lobe, has led to increased energy demands, making the brain vulnerable to metabolic disruptions seen in ASD. Mitochondrial dysfunction in ASD is characterized by impaired oxidative phosphorylation, elevated lactate and alanine levels, carnitine deficiency, abnormal reactive oxygen species, and altered calcium homeostasis. These dysfunctions are primarily functional rather than due to mitochondrial DNA mutations. Calcium signaling plays a crucial role in neuronal ATP production, with disruptions in ITPR-mediated ER calcium release observed in ASD patient-derived cells. This impaired signaling affects the ER-mitochondrial calcium axis, leading to mitochondrial energy deficiency, particularly in high-energy regions of the developing brain. The BTBR mouse model, with a unique Itpr3 gene mutation, exhibits core autism-like behaviors and metabolic syndromes, providing valuable insights into ASD pathophysiology. Various interventions have been tested in BTBR mice, as in ASD, but none have directly targeted the Itpr3 mutation or its calcium signaling pathway. This review highlights the need for further research into metabolic resilience and calcium signaling as potential diagnostic and therapeutic targets for ASD.