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

Journal of Molecular Medicine https://doi.org/10.1007/s00109-020-02018-2 REVIEW Abnormalities of synaptic mitochondria in autism spectrum disorder and related neurodevelopmental disorders Liliana Rojas-Charry 1,2,3 & Leonardo Nardi 1 & Axel Methner 2,3 & Michael J. Schmeisser 1,3 Received: 3 September 2020 / Revised: 27 November 2020 / Accepted: 2 December 2020 # The Author(s) 2020 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 Autism spectrum disorder . ASD . Synapse . Mitochondria . Neurodevelopmental disorders Introduction Autism spectrum disorder (ASD) is a neurodevelopmental condition that starts in childhood and prevails across the lifespan, symptoms are variable, and a substantial increase in ASD diagnosis has been reported during the last 40 years [1]. A significant part of ASD cases is associated with mutations in synaptic proteins, suggesting an impairment of synaptic transmission as a primary underlying cause [2–7]. Synaptic activity is an energetically expensive process that consumes a large proportion of the adenosine triphosphate (ATP) generated in neurons, which is mainly produced by mitochondria through * Axel Methner * Michael J. Schmeisser 1 Institute for Microscopic Anatomy and Neurobiology, University Medical Center of the Johannes Gutenberg-University, Duesbergweg 6, 55128 Mainz, Germany 2 Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University, Langenbeckstraße 1, 55131 Mainz, Germany 3 Focus Program Translational Neurosciences (FTN), University Medical Center of the Johannes Gutenberg-University, Mainz, Germany oxidative phosphorylation (OXPHOS) [8]. Mitochondria are present in approximately half of all presynaptic boutons, and synapses that contain mitochondria have more vesicles [9]. Postsynaptic mitochondria are less abundant and have a more tubular form than presynaptic mitochondria [10], indicating that distinct morphological changes in dendrites and axons occur to adjust their shape to energetic or other needs [11]. In addition, local synthesis of new proteins occurs in axons and dendrites and depends on mitochondria that provide energy during synaptic plasticity [12]. Besides their role as energy providers, mitochondria also act as calcium (Ca2+) buffers that shape the synaptic response [13]. Hence, their presence at the synapse serves not only to produce ATP but also to control local Ca2+ concentrations ([Ca2+]) and neurotransmitter release, which is essentially triggered by a sudden increase in Ca2+ concentration. The synaptic [Ca2+] is tightly regulated by efflux through the plasma membrane and uptake into the spine apparatus, a sub-compartment of the smooth endoplasmic reticulum (sER), and mitochondria [14–17]. Genetically encoded Ca2+ sensors have provided evidence that individual hippocampal and cortical synapses with mitochondria accumulate less synaptic Ca2+ than those lacking these organelles [18, 19]. Based on the importance of synaptic signaling in ASD and the relevance of mitochondria in synaptic activity, we here aim to summarize the current knowledge about the role of synaptic mitochondria in ASD and other ASD-related neurodevelopmental disorders. J Mol Med Functions of neuronal and synaptic mitochondria The brain consumes large amounts of oxygen—20% of the whole body’s consumption—and most of this oxygen is used to generate ATP through OXPHOS in mitochondria [8]. Mitochondria provide 93% of the ATP that the brain demands [20]. This ATP is used to support synaptic transmission, a very energy-demanding process. ATP is necessary to power ion pumps, support ion gradients, and maintain vesicle recycling and mitochondrial movement. Remarkably, the number of mitochondria in synaptic terminals and axons exceeds the predicted energy needs [20], which implies that they have additional functions at the synapse, like the buffering of intra-spine Ca2+ levels that directly influence the firing probability of neurons [14, 21]. The function of mitochondria as Ca2+ buffers and ATP producers also relies on the ER [22], which stores the highest concentrations of Ca2+ ions. The points of contact between the ER membrane and mitochondria are called mitochondria-ER contact sites (MERCs) or mitochondria-associated membranes (MAMs) [23]. MAMs are crucial for controlling Ca2+ concentrations in neurons through the ER channels inositol 1,4,5-trisphosphate receptors (IP3R), the sarcoendoplasmicreticulum Ca2+ ATPase (SERCA), the glucose-regulated protein 75 (Grp75), the voltage-dependent anion channel (VDAC1), and the mitochondrial Ca2+ uniporter (MCU) [24]. Another Ca2+ modulator, the receptor chaperone Sigma 1 (S1R), localizes in MAMs in a complex with type 3 IP3R [25]. Other tethering complexes are formed by proteins like the protein tyrosine phosphatase-interacting protein 51 (PTPIP51), the vesicle-associated membrane proteinassociated protein B (VAPB), and the B cell receptor– associated protein (BAP31), which are also associated with Ca2+ handling [26]. Interestingly, mutations in VAPB and S1R are related to neurodegenerative diseases [27, 28]. MAMs are frequent in neurons, and besides the regulation of Ca2+ signaling, they are involved in synaptic transmission, since the absence of VAPB-PTPIP51 in synapses leads to a reduced number of dendritic spines and decreased synaptic activity [29, 30]. Cytosolic Ca2+ ions that enter the mitochondrial matrix through the MCU increase OXPHOS by stimulating pyruvate dehydrogenase phosphatase rendering the pyruvate dehydrogenase complex more active [31]. Ca2+ also activates other citrate cycle enzymes, like isocitrate dehydrogenase and alpha-ketoglutarate dehydrogenase [32, 33]. Besides MCU, additional mitochondrial uptake mechanisms have been identified in heart and liver cells, like the mitochondrial ryanodine receptor (mRyR) and the rapid mode of uptake (RaM) [34–36]. Ca2+ release into the cytosol is executed through either the mitochondrial permeability transition pore (mPTP) or the Na+/Ca2+ exchanger (mNCX) [37, 38]. The increase in cytosoli (...truncated)