The dynamic mitochondria network in neurodegeneration

Abstract

Mitochondrial fragmentation due to fission/fusion imbalance has often been linked to mitochondrial dysfunction and apoptosis in neurodegeneration. It is traditionally believed that once the morphology of mitochondria shifts away from its physiological tubular form, mitochondria becomes defective and downstream apoptotic signalling pathways are triggered. In this study, we explored the dynamic changes in mitochondrial network in neurodegeneration. Our study showed that at early stages of neurodegeneration, beta-amyloid (Ab ) induced morphological changes in mitochondria where they become granular shape which was distinct from the conventional round and fragmented mitochondria in terms of both morphology and function. In addition, we demonstrated that accumulation of mitochondrial reactive oxygen species triggered granular mitochondria formation, while mitoTEMPO (a mitochondria-targeted superoxide scavenger) restored tubular mitochondrial morphology within Ab -treated neurons. Interestingly, modulations of mitochondria fission and fusion by genetic and pharmacological means not only attenuated the induction of granular mitochondria but also diminished mitochondrial superoxide levels in Ab -treated neurons. This study demonstrates a unique reciprocal relationship between mitochondrial dynamics and reactive oxygen species and provides a new possible therapeutic target at early stages of neurodegenerative disease pathogenesis. This study is supported by HMRF02131956, HKU Alzheimer’s Disease Research Network, and generous donation from Ms. Kit-Wan Chow.