Genetic Dissection of Energy Deficiency in Autism Spectrum Disorder.

This review explores how energy problems in the brain might contribute to autism. Researchers found that people with autism often have issues with their cells' energy factories (mitochondria) and calcium signaling systems. These problems affect how brain cells produce and use energy, which may contribute to autism symptoms. The researchers used a mouse model of autism to better understand these energy problems and suggest this could lead to new treatments.

This review examines energy deficiency mechanisms in autism spectrum disorder (ASD), focusing on mitochondrial dysfunction and calcium signaling abnormalities. The authors propose that rapid human brain evolution, particularly in the parietal lobe, created increased energy demands that make the brain vulnerable to metabolic disruptions seen in ASD. Key findings include impaired oxidative phosphorylation, elevated lactate and alanine levels, carnitine deficiency, abnormal reactive oxygen species, and altered calcium homeostasis in ASD. These dysfunctions are primarily functional rather than genetic.

The BTBR mouse model provides insights into ASD pathophysiology through its unique gene mutation and metabolic syndromes. The review highlights calcium signaling disruptions affecting the ER-mitochondrial calcium axis, leading to energy deficiency in high-energy brain regions during development.

Findings suggest potential for developing metabolic interventions targeting mitochondrial function and calcium signaling in ASD. The functional nature of mitochondrial dysfunction indicates possible reversibility through targeted therapies. Research highlights the need for further investigation into metabolic resilience and calcium signaling as diagnostic and therapeutic targets.

This is a review article synthesizing existing research rather than presenting new empirical data. The abstract does not specify the methodology for literature selection or quality assessment. Sample sizes and study designs of included research are not detailed.

: An important new consideration when studying autism spectrum disorder (ASD) is the bioenergetic mechanisms underlying the relatively recent rapid evolutionary expansion of the human brain, which pose fundamental risks for mitochondrial dysfunction and calcium signaling abnormalities and their potential role in ASD, as recently highlighted by insights from the BTBR mouse model of ASD. The rapid brain expansion taking place asevolved, particularly in the parietal lobe, led to increased energy demands, making the brain vulnerable to such metabolic disruptions as are seen in ASD.: Mitochondrial dysfunction in ASD is characterized by impaired oxidative phosphorylation, elevated lactate and alanine levels, carnitine deficiency, abnormal reactive oxygen species (ROS), and altered calcium homeostasis. These dysfunctions are primarily functional, rather than being due to mitochondrial DNA mutations. Calcium signaling plays a crucial role in neuronal ATP production, with disruptions in inositol 1,4,5-trisphosphate receptor (ITPR)-mediated endoplasmic reticulum (ER) calcium release being 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 its uniquegene 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 themutation or its calcium signaling pathway. This review presents current genetic, biochemical, and neurological findings in ASD and its model systems, highlighting the need for further research into metabolic resilience and calcium signaling as potential diagnostic and therapeutic targets for ASD.