Mitochondria and Neurobiology

Abnormal proteostasis, dysfunctional mitochondria, and aberrant redox signalling are often associated in neurodegenerative disorders. We investigated how changes in redox signalling affect proteostasis mechanisms - including protein degradation pathways and unfolded protein responses - by testing the mitochondria-targeted antioxidant MitoQ in HD mice. We showed that abnormal redox signalling in muscle contributes to altered proteostasis and motor impairment, and that redox interventions can improve muscle performance, highlighting the importance of peripheral therapeutics in HD (Pinho et al 2020 Free Rad Biol Med 146:372-382).

Superoxide generation by mitochondria is a major source of reactive oxygen species (ROS) which are capable of initiating redox signaling and oxidative damage. The current understanding of the role of mitochondrial ROS in health and disease has been limited by the lack of experimental strategies to selectively induce mitochondrial superoxide production. We performed a first in vivo study of the recently-developed mitochondria-targeted redox cycler MitoParaquat (MitoPQ) in the vertebrate zebrafish model and in a human cell model of Huntington's disease (HD). MitoPQ induced a parkinsonian phenotype in zebrafish, with decreased reflexes, spontaneous movement and dopaminergic neurodegeneration, without detectable effects on heart rate or atrioventricular coordination. In a HD cell model, MitoPQ promoted mutant huntingtin aggregation without increasing cell death. These results show that MitoPQ is a valuable tool for cellular and in vivo studies of the role of mitochondrial superoxide generation in redox biology, and as a trigger or co-stressor to model metabolic and neurodegenerative disease phenotypes (Pinho et al 2019 Free Rad Biol Med 130:318-327).