Altered Mitochondrial Unfolded Protein Response and Protein Quality Control promote oxidative distress in Down Syndrome brain

Free Radical Biology and Medicine, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 1, 2024

Down Syndrome (DS) is a genetic disorder caused by the presence of an extra copy chromosome 21, and leading to various developmental cognitive defects. A critical feature DS occurrence oxidative distress particularly in brain, which exacerbates neurodevelopmental processes. Mitochondria play crucial role cell energy metabolism their impairment one major causes several pathologies. Hence, this study investigates mitochondrial proteostasis mean Unfolded Protein Response (UPRmt) protein quality control (MQC) mechanisms context DS, focusing on implications redox homeostasis brain development. We analyzed key UPRmt markers function frontal cortex isolated fromTs2Cje mice, model for across different stages. Our results demonstrate significant alterations markers, at postnatal day 0 (P0) 1 month (1M). These changes indicate early activation, primarily driven ATF5/GRP75 axis, although compromised reduced levels other components. Impaired correlates with decreased activity, evidenced oxygen consumption rates altered expression OXPHOS complexes. Additionally, elevated stress such as 3-nitrotyrosine (3-NT), 4-hydroxynonenal (HNE), carbonyls (PC) were observed, linking dysfunction increased damage. Defects MQC, including disrupted biogenesis, fission, activation mitophagy evident mostly P0 1M consistent activation. Principal Component Analysis revealed distinct phenotypic differences between Ts2Cje these molecular alterations. findings underscore MQC development, highlighting potential therapeutic targets mitigate distress, thereby alleviating some impairments associated DS.

Language: Английский

The 9 bp Deletion between the Mitochondrial COII and Lysine tRNA Genes in a Caucasian Population with Cognitive Disorders: An Observational Study

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(19), P. 10826 - 10826

Published: Oct. 9, 2024

The loss of one the two copies 9 bp tandem repeat sequence (CCCCCTCTA) located in small non-coding region between cytochrome oxidase II (COII) and lysine tRNA genes human mtDNA has been reported to be polymorphic Asian, Oceanian Sub-Saharan African populations, but it rarely observed Europe. In this study, we will evaluate possible association MIC9D polymorphism cognitive disorders. A genetic analysis unrelated Sicilian patients with deficits was performed identify deletion polymorphism. found six patients, whereas variant absent control individuals without deficits. exhibited more complex clinical presentations; particular, all had neuromuscular disorders five also presented behavioral present study suggests a potential impairment concurrent involvement.

Language: Английский