Early dynamic changes of mitochondrial morphology in hippocampal neurons in response to β-amyloid

Abstract

Neurons are particularly vulnerable to mitochondrial dysfunction due to their high demand of energy. Abnormal mitochondrial dynamics (fission, fusion and movement) has been implicated in the pathogenesis of neurodegenerative diseases including Alzheimer’s disease (AD). Fragmentation of tubular mitochondrial network into spherical organelles during apoptosis has often been linked with mitochondrial dysfunction. However, the relationship between mitochondrial morphology and functions remains obscure; and it is unclear if mitochondrial fragmentation is a straightforward process in disease progression. We hypothesize that early morphological changes of mitochondria do not represent dysfunction of mitochondria. Our aim is to elucidate what are the morphological changes of mitochondria and the inducing factors for such changes. Here, we report that oligomeric beta amyloid (Aβ) induces dynamic changes of mitochondrial morphology at different time points. Aβ triggers morphological changes in mitochondria at early time points (1-6 h), resulting in granular-shaped mitochondria. Despite an obvious change in shape, there are no significant changes in mitochondrial membrane potential and ADP/ATP ratio in granular mitochondria. These granular-shaped mitochondria are morphologically and functionally distinct from fragmented spherical mitochondria during apoptosis. Both treatment of oxidative stress inducing agents and laser-induced mitochondrial-specific oxidative stress by KillerRed-Mito induce granular mitochondria in neurons. These data demonstrate that granular mitochondria might be a result of early oxidative stress in mitochondria. From 6 h onwards, mitochondria undergo dynamic changes in their morphologies according to different cell conditions, and eventually become circular in shape. Our study provides new perspective in mitochondrial morphology and functions at different stages of disease pathogenesis.