skip to content

MRC Mitochondrial Biology Unit

 

Recent research from the group has been selectively highlighted in Life Science Alliance’s Neuroscience Collection 2024 (a "special collection of articles recently published in LSA highlighting some of the latest advances in neuroscience”), and will also be featured in a special magazine that LSA are distributing at SfN next week. The paper was in the LSA top 10 most read LSA articles for 3 months and an image from the paper was also chosen as the ‘cover image’ for the Collection. 

Amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) is a devastating spectrum disorder that can variously rob patients of their ability to move and/or affect cognitive ability and personality traits. Mitochondrial dysfunction is frequently observed in models of C9orf72 mutations - the most common cause of ALS/FTD. However, it was unclear which aspects of mitochondrial dysfunction may be a cause or consequence of the pathogenic process. 
Analysing multiple aspects of mitochondrial biology across several Drosophila models of C9orf72-ALS/FTD, we found morphology, oxidative stress, and mitophagy are commonly affected, which correlated with progressive loss of locomotor performance. Notably, only genetic manipulations that reversed the oxidative stress levels were also able to rescue C9orf72 locomotor deficits, supporting a causative link between mitochondrial dysfunction, oxidative stress, and behavioural phenotypes. 
 
Targeting the key antioxidant Keap1/Nrf2 pathway, we found that genetic reduction of Keap1 or pharmacological inhibition by dimethyl fumarate significantly rescued the C9orf72-related oxidative stress and motor deficits. Finally, mitochondrial ROS levels were also elevated in C9orf72 patient-derived iNeurons and were effectively suppressed by dimethyl fumarate treatment. 
 
These results show that mitochondrial oxidative stress is an important mechanistic contributor to C9orf72 pathogenesis, affecting multiple aspects of mitochondrial function and turnover. Targeting the Keap1/Nrf2 signalling pathway to combat oxidative stress represents a therapeutic strategy for C9orf72-related ALS/FTD.
 
Au WH, Miller-Fleming L, Sanchez-Martinez A, Lee JA, Twyning MJ, Prag HA, Raik L, Allen SP, Shaw PJ, Ferraiuolo L, Mortiboys H, Whitworth AJ.
Life Sci Alliance. 2024 Jun 21;7(9):e202402853. doi: 10.26508/lsa.202402853. Print 2024 Sep.
PMID: 38906677