Background: Mitochondrial dysfunction is a pathogenetic mechanism in neurodegenerative disease, including amyotrophic lateral sclerosis (ALS). Specifically, alterations in bioenergetics and mitochondrial function have been described in animal and cellular models of ALS as well as in patient samples. Studies in Alzheimer’s disease have linked mitochondrial dysfunction to interactions between hyperphosphorylated tau (pTau) and dynamin-related protein 1 (DRP1), the GTPase involved in mitochondrial fission. However, it is yet unclear if this interaction occurs in ALS and leads to alterations in mitochondrial morphology and function.
Objective: To determine whether DRP1 and pTau cause mitochondrial fragmentation and dysfunction in ALS.
Results: Our findings revealed that there are significantly fewer and shorter mitochondria in ALS mCTX together with a significant increase in DRP1 in synaptoneurosomes (SNs) derived from ALS mCTX. Importantly, increases in DRP1 were independent of sex, region of onset, and genotype. Furthermore, co-immunoprecipitation experiments demonstrated an interaction between DRP1 and pTau suggesting that pTau may contribute to mitochondria fragmentation in ALS. Importantly, while treatment of SH-SY5Y cells with ALS SNs, enriched in both DRP1 and pTau, resulted in a significant decrease in mitochondrial length, volume, and networks, reducing DRP1 using siRNA reversed these deficits in mitochondrial morphology. Lastly, treatment of SH-SY5Y cells with QC-01-175, a novel tau degrader, also rescued the deficits in mitochondrial length and volume induced by ALS SNs.
Conclusions: Collectively, our results indicate that increases in both DRP1 and pTau may cause mitochondrial fragmentation in ALS leading to an unfavorable energetic state and contribute to motor neuron loss.