A reciprocal relationship between reactive oxygen species and mitochondrial dynamics in neurodegeneration

Mitochondrial fragmentation due to fission/fusion imbalance has often been linked to mitochondrial dysfunction and apoptosis in neurodegeneration. Conventionally, it is believed that once mitochondrial morphology shifts away from its physiological tubular form, mitochondria become defective and downstream apoptotic signaling pathways are triggered. However, our study shows that beta-amyloid (Aβ) induces morphological changes in mitochondria where they become granular-shaped and are distinct from fragmented mitochondria in terms of both morphology and functions. Accumulation of mitochondrial reactive oxygen species triggers granular mitochondria formation, while mitoTEMPO (a mitochondria-targeted superoxide scavenger) restores tubular mitochondrial morphology within Aβ-treated neurons. Interestingly, modulations of mitochondria fission and fusion by genetic and pharmacological tools attenuated not only the induction of granular mitochondria, but also mitochondrial superoxide levels in Aβ−treated neurons. Our study shows a reciprocal relationship between mitochondrial dynamics and reactive oxygen species and provides a new potential therapeutic target at early stages of neurodegenerative disease pathogenesis. [Display omitted] •Aβ induces granular mitochondria at early stages of neurodegeneration.•Mitochondrial ROS triggers aberrant mitochondrial dynamics & granular mitochondria.•Granular mitochondria is reversible and attenuated by mitoTEMPO.•Manipulation of mitochondrial dynamics abolishes formation of granular mitochondria, but also reduces super oxide levels in mitochondria.•Manipulation of mitochondrial dynamics reduces super oxide levels in mitochondria.