Autism spectrum disorders: an impaired glycolysis induces an ATP deficiency and a reduced cell respiration - Nasal Olfactory Stemness and Epigenesis
Pré-Publication, Document De Travail Année : 2024

Autism spectrum disorders: an impaired glycolysis induces an ATP deficiency and a reduced cell respiration

Résumé

In two previous studies, based on human olfactory ecto-mesenchymal stem cells (OE-MSC) of 11 paQents with auQsm spectrum disorders (ASD) and 11 healthy individuals, we demonstrated that the lower abundance of the enzyme MOCOS (MOlybdenum COfactor Sulfurase) and its associated lower expression of the long non-coding RNA, COSMOC, induces neurotransmission and synapQc defects as well as an exacerbated oxidaQve stress sensiQvity.

To move a step further, we assessed whether these defects were associated to a disturbed mitochondrial homeostasis. For that purpose, we used cellular and molecular techniques to quanQ^y mitochondrial metabolism and biogenesis, ATP producQon and cell respiraQon in OE-MSCs from the 8 ASD paQents of the cohort that display the most severe symptoms. We show here that OE-MSCs from ASD paQents, when compared to control individuals, display i) a reduced expression/abundance of glycolysis-associated transcripts and metabolites, ii) an overall reduced ATP, mainly due to the impaired glycolysis, iii) a reduced basal cell respiraQon and iv) a modified mitochondrial network. These results are in accordance with some of our previously published data and may explain some of the symptoms -stress, overarousal, seizures, increased or decreased muscle tone, faQgue -observed in auQsm spectrum disorders.

Introduc.on

AuQsm Spectrum Disorders (ASD), which affect around 50 million individuals worldwide (Hahler and Elsabbagh 2015), is a major public health issue. With an onset under the age of three, ASD are understood as diseases arising from pre-and/or early post-natal brain developmental anomalies and/or early brain insults/infecQons. To unveil the molecular mechanisms at play during the misshaping of the developing brain, we chose to study cells representaQve of the very early stages of ontogeny, namely adult stem cells and, more specifically, human nasal olfactory stem cells (Delorme et al. 2010). In a first series of experiments, based on a cohort of 11 auQsQc paQents and 11 healthy individuals we demonstrated the reduced expression/producQon of MOCOS and MOCOS (MOlybdenum COfactor Sulfurase), an enzyme involved in purine metabolism 3 , and its associated long noncoding RNA that we named COSMOC 4 . We observed that reduced expression of MOCOS and/or COSMOC induces neurotransmission and synapQc defects as well as an exacerbated oxidaQve stress sensiQvity (Féron et al. 2016; Rontani et al. 2021).

All these molecules are involved in the synthesis of molybdenum enzymes, which begins in mitochondria with the conversion of guanosine triphosphate (GTP) to cyclic pyranopterin monophosphate (cPMP) by the two acQve forms of the MOCS1 enzyme (MOCS1A and MOCS1AB) (Mendel and Kruse 2012). cPMP is then converted outside the mitochondria via MOCS2 to molybdopterin (MPT), which in turn is further converted to the MOlybdenum COfactor (MOCO) by gephyrin (GPHN). MOCO is the central element of the four human molybdenum enzymes: i) sulfite oxidase (SUOX) that transforms sulfites into sulfates (Mendel and Schwarz 2023); ii) xanthine dehydrogenase (XDH) and aldehyde oxidase (AOX) that catalyse the two-step reacQon from hypoxanthine to xanthine and from xanthine to uric acid in purine metabolism (Bortoloj et al. 2021); iii), and is involved in the metabolism of reQnaldehyde, respecQvely, and the mitochondrial amidoxime-reducing component (mARC), a key factor in the N-hydroxylaQon of prodrugsor N-oxygenated compounds (Struwe, Scheidig, and Clement 2023).

Many observaQons have linked auQsm disorders to mitochondrial dysfuncQon (for a review, (Nabi et al. 2023)). An exploratory study reported that the majority of lymphocytes from very young ASD children exhibit a reduced acQvity of oxidaQve phosphorylaQon as well as a mitochondrial DNA over-replicaQon (Giulivi et al. 2010). In addiQon to mutaQons in

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Dates et versions

hal-04768741 , version 1 (06-11-2024)

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  • HAL Id : hal-04768741 , version 1

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Francois Féron, Damien Caillol, Laure Fourel, Silke Leimkuhler, Olga Iranzo, et al.. Autism spectrum disorders: an impaired glycolysis induces an ATP deficiency and a reduced cell respiration. 2024. ⟨hal-04768741⟩
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