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Updated: Nov 11, 2025
Author Spotlight: Exploring Mitochondrial Function and Chemical Toxicity Using Drosophila melanogaster
Published on: November 10, 2023
TDP-43 and PINK1 mediate CHCHD10S59L mutation-induced defects in Drosophila and in vitro
Minwoo Baek1, Yun-Jeong Choe1, Sylvie Bannwarth2
1Department of Pharmacy Practice and Pharmaceutical Sciences, College of Pharmacy, University of Minnesota, Duluth, MN, USA.
Insights
Mutations in CHCHD10 cause ALS-FTD through mitochondrial defects and TDP-43 pathway disruption. Targeting TDP-43 translocation and PINK1 pathways may offer therapeutic strategies for this neurodegenerative disease.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Mutations in coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10) are linked to amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD).
- The precise molecular mechanisms driving CHCHD10-associated neurodegeneration remain largely unknown.
Purpose of the Study:
- To investigate the cellular and molecular mechanisms underlying CHCHD10-associated ALS-FTD.
- To model CHCHD10-associated ALS-FTD using Drosophila melanogaster and HeLa cell lines expressing the CHCHD10S59L mutation.
Main Methods:
- Generation of CHCHD10S59L-mutant Drosophila and HeLa cell models.
- Assessment of cellular toxicity and mitochondrial function.
- Analysis of the interplay between CHCHD10S59L, TDP-43, and the PINK1 pathway.
Main Results:
- The CHCHD10S59L mutation induces significant cell toxicity and mitochondrial dysfunction.
- CHCHD10S59L expression promotes TDP-43 insolubility and its translocation to mitochondria.
- Inhibition of TDP-43 mitochondrial translocation ameliorates CHCHD10S59L-mediated toxicity.
- Modulation of the PINK1 pathway rescues phenotypes and mitigates mitochondrial defects in both model systems.
Conclusions:
- CHCHD10S59L-induced TDP-43 mitochondrial translocation and chronic PINK1 pathway activation contribute to dominant toxicity in ALS-FTD.
- These findings provide crucial mechanistic insights into CHCHD10 mutations linked to ALS-FTD.
- The study highlights potential therapeutic targets, including TDP-43 translocation and PINK1 signaling.
Abstract:
Mutations in coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10) can cause amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). However, the underlying mechanisms are unclear. Here, we generate CHCH10S59L-mutant Drosophila melanogaster and HeLa cell lines to model CHCHD10-associated ALS-FTD. The CHCHD10S59L mutation results in cell toxicity in several tissues and mitochondrial defects. CHCHD10S59L independently affects the TDP-43 and PINK1 pathways. CHCHD10S59L expression increases TDP-43 insolubility and mitochondrial translocation. Blocking TDP-43 mitochondrial translocation with a peptide inhibitor reduced CHCHD10S59L-mediated toxicity. While genetic and pharmacological modulation of PINK1 expression and activity of its substrates rescues and mitigates the CHCHD10S59L-induced phenotypes and mitochondrial defects, respectively, in both Drosophila and HeLa cells. Our findings suggest that CHCHD10S59L-induced TDP-43 mitochondrial translocation and chronic activation of PINK1-mediated pathways result in dominant toxicity, providing a mechanistic insight into the CHCHD10 mutations associated with ALS-FTD.
