Abnormalities of synaptic mitochondria in autism spectrum disorder and related neurodevelopmental disorders

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental condition primarily characterized by an impairment of social interaction combined with the occurrence of repetitive behaviors. ASD starts in childhood and prevails across the lifespan. The variability of its clinical presentation renders early diagnosis difficult. Mutations in synaptic genes and alterations of mitochondrial functions are considered important underlying pathogenic factors, but it is obvious that we are far from a comprehensive understanding of ASD pathophysiology. At the synapse, mitochondria perform diverse functions, which are clearly not limited to their classical role as energy providers. Here, we review the current knowledge about mitochondria at the synapse and summarize the mitochondrial disturbances found in mouse models of ASD and other ASD-related neurodevelopmental disorders, like DiGeorge syndrome, Rett syndrome, Tuberous sclerosis complex, and Down syndrome.

Keywords: ASD; Autism spectrum disorder; Mitochondria; Neurodevelopmental disorders; Synapse.

Fig. 1

Mitochondrial-ER contact sites in neurons. The endoplasmic reticulum (ER) and mitochondria are connected by several proteins depicted here. Mitofusin 2 (Mfn2) regulates the tethering between the two organelles by a direct interaction through its heptad repeat domains (HR)[40]. Mitofusin 1 (Mfn1) participates in this process and remains in the mitochondria. Other proteins like tyrosine phosphatase-interacting protein 51 (PTPIP51) and the vesicle-associated membrane protein-associated protein B (VAPB) also build bridges to connect both organelles [26]. The mitochondrial fission protein (Fis1) forms a complex with the B cell receptor–associated protein (BAP31) that signals for apoptosis [41]. The sarcoendoplasmic-reticulum Ca²⁺ ATPase (SERCA) transports Ca²⁺ into the ER. The Ca²⁺ release channel, inositol 1,4,5-trisphosphate receptor (IP3R), is composed of 4 subunits [42] and interacts with a Ca²⁺ modulator, the receptor chaperone Sigma 1 (S1R). The ryanodine receptor (RyR) is another Ca²⁺ release channel. Ca²⁺ ions enter the mitochondrial matrix through the mitochondrial calcium uniporter (MCU) and activate enzymes that stimulate the tricarboxylic acid (TCA) cycle and the electron transport chain (ETC) [–33]. Excessive Ca²⁺ ions are released into the cytosol through the mitochondrial permeability transition pore (mPTP) and the Na⁺/Ca²⁺ exchanger (mNCX) [37, 38]. Arrows indicate the direction of Ca²⁺ flow. Created with BioRender.com

Fig. 2

Synapse structure and mitochondria. The figure represents some of the recognized mitochondrial functions in a glutamatergic synapse. Presynaptic mitochondria are smaller and more abundant than postsynaptic mitochondria in the hippocampus [86]. Postsynaptic mitochondria have dense cristae, and tubular shapes, and make contacts with the ER [10, 87]. Mitochondrial movement increases in axons and is greater than in dendrites, although some mitochondria remain stationary (represented by the absence of mitochondrial motors) [88]. Not all of the presynaptic boutons contain mitochondria (only less than half), but the synapses with mitochondria have more vesicles and are associated with increased synaptic activity [9, 89]. Augmented Ca²⁺ concentrations are detected in microdomains (depicted in ovals) [90]. Neurexin, Neuroligin, and SHANK are synaptic scaffolding proteins implicated in ASD [91]. Abbreviations: PSD-95 (postsynaptic density protein 95); GKAP (guanylate kinase-associated protein). Created with BioRender.com

Fig. 3

Mitochondrial disturbances in different brain regions of mouse models of ASD. The figure provides an overview of the mitochondrial defects found in the cortex/prefrontal cortex (PFC), striatum, hippocampus, and cerebellum in different ASD mouse models. Arrows point to the specific mitochondrial disturbances found in the different mouse models in a cortex and PFC; b striatum; c hippocampus and d cerebellum. Dotted blue lines delineate the specific brain regions. Most of the studies are focused on hippocampal mitochondria; the mitochondrial phenotype has been most extensively studied in Fmr1 and Mecp2 mutant mouse models. Created with BioRender.com