Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Relationships Between Mitochondrial Function, AMPK and TORC1 Signalling in Lymphoblasts with Premutation Alleles of the FMR1 Gene

Version 1 : Received: 23 September 2021 / Approved: 23 September 2021 / Online: 23 September 2021 (11:10:47 CEST)

A peer-reviewed article of this Preprint also exists.

Fisher, P.R.; Allan, C.Y.; Sanislav, O.; Atkinson, A.; Ngoei, K.R.W.; Kemp, B.E.; Storey, E.; Loesch, D.Z.; Annesley, S.J. Relationships between Mitochondrial Function, AMPK, and TORC1 Signaling in Lymphoblasts with Premutation Alleles of the FMR1 Gene. Int. J. Mol. Sci. 2021, 22, 10393. Fisher, P.R.; Allan, C.Y.; Sanislav, O.; Atkinson, A.; Ngoei, K.R.W.; Kemp, B.E.; Storey, E.; Loesch, D.Z.; Annesley, S.J. Relationships between Mitochondrial Function, AMPK, and TORC1 Signaling in Lymphoblasts with Premutation Alleles of the FMR1 Gene. Int. J. Mol. Sci. 2021, 22, 10393.

Journal reference: Int. J. Mol. Sci. 2021, 22, 10393
DOI: 10.3390/ijms221910393

Abstract

The X-linked FMR1 gene contains a non-coding trinucleotide repeat in its 5’ region that in normal, healthy individuals contains 20-44 copies. Large expansions of this region (>200 copies) cause fragile X syndrome (FXS), but expansions of 55-199 copies (referred to as premutation alleles) predispose carriers to a neurodegenerative disease called fragile X-associated tremor/ataxia syndrome (FXTAS). The cytopathological mechanisms underlying FXTAS are poorly understood, but abnormalities in mitochondrial function are believed to play a role. We previously reported that lymphoblastoid cell lines (LCLs, or lymphoblasts) of premutation carriers have elevated mitochondrial respiratory activities. In the carriers, especially those not clinically affected with FXTAS, AMPK activity was shown to be elevated. In the FXTAS patients, however, it was negatively correlated with brain white matter lesions, suggesting a protective role in the molecular mechanisms. Here we report an enlarged and extended study of mitochondrial function and associated cellular stress-signalling pathways in lymphoblasts isolated from male and female premutation carriers, regardless of their clinical status, and healthy controls. The results confirmed the elevation of AMPK and mitochondrial respiratory activities and reduction of reactive O2 species (ROS) levels in premutation cells and revealed for the first time that TORC1 activities are reduced. Extensive correlation, multiple regression and Principal Components analysis revealed the best fitting statistical explanations of these changes in terms of the other variables measured. These suggested which variables might be the most “proximal” regulators of the others in the extensive network of known causal interactions amongst the measured parameters of mitochondrial function and cellular stress signalling. In the resulting model, the premutation alleles activate AMPK and inhibit both TORC1 and ROS production, the reduced TORC1 activity contributes to activation of AMPK activation and of nonmitochondrial metabolism, and the higher AMPK activity results in elevated catabolic metabolism, mitochondrial respiration and ATP steady state levels. In addition the results suggest a separate CGG repeat number-dependent elevation of TORC1 activity that is insufficient to overcome the inhibition of TORC1 in premutation cells, but may presage the previously reported activation of TORC1 in FXS cells.

Keywords

AMPK; TOR Complex I; mitochondria; FMR1; Fragile X-associated Tremor/Ataxia Syndrome (FXTAS); CGG trinucleotide repeat

Comments (0)

We encourage comments and feedback from a broad range of readers. See criteria for comments and our diversity statement.

Leave a public comment
Send a private comment to the author(s)
Views 0
Downloads 0
Comments 0
Metrics 0


×
Alerts
Notify me about updates to this article or when a peer-reviewed version is published.
We use cookies on our website to ensure you get the best experience.
Read more about our cookies here.