Characterization of mitochondrial morphology and dynamics in neurodegeneration

Abstract

Mitochondria are ubiquitous organelles which are crucial for life and death pathways in the cell, including ATP production, Ca2+ homeostasis, and regulation of apoptosis. Dynamics of mitochondrial network (fission, fusion, and transport) are important for maintaining proper functions of the organelle. Mitochondria continuously undergo fission and fusion to regulate their morphology, distribution, turnover, and transportation within the cell. Heterogeneity of mitochondrial morphology has been described within and between cells. Furthermore, increasing lines of evidence have shown distinct shapes of mitochondria in response to different stress stimuli. Recently, abnormal mitochondrial dynamics have been implicated in various neurodegenerative diseases. Alzheimer’s disease (AD) is a devastating neurodegenerative disorder affecting over 36 millions of people worldwide. In AD, patients suffer from gradual deteriorations in cognitive abilities, which eventually lead to death. With over a hundred years of research, the underlying mechanisms of this incurable disease remain obscure. In the current study, the role of mitochondrial dynamics in AD was investigated. During apoptosis, tubular mitochondrial network breaks into punctate spheres in which the process is often referred as mitochondrial fragmentation. While mitochondrial fragmentation is an important pathological event at later stages of neurodegeneration, the role of mitochondrial dynamics at early stages of disease progression is not well understood. Moreover, the relationship between mitochondrial morphology and functions remains obscure. Furthermore, it is unclear if mitochondrial fragmentation is a straightforward process in the course of neurodegeneration. In this study, the temporal effects of I-Amyloid (A-) on mitochondrial morphology and functions were investigated. At early time points following AAAtreatments, mitochondria rapidly transformed from tubular to granular morphology. The induction of granular mitochondria was shown to be associated with increase in mitochondrial oxidative stress induced by A Using simultaneous photoactivation and fluorescence recovery after photobleaching (SPA-FRAP), mitochondrial dynamics were found to be impaired by Am-induced oxidative stress. Despite the drastic changes in morphology, mitochondrial functions remained intact. Thus, changes in organelle morphology do not necessarily accompany impairment in organelle functions. Furthermore, the induction of granular mitochondria could be abolished by inhibition of fission, suggesting that it might be a transient process. Granular mitochondria were defined as a novel phenotype of mitochondria, which is morphologically and functionally distinct from mitochondrial fragmentation in apoptosis. With prolonged Anntreatment, mitochondria exhibited a variety of distinct morphologies, including short and elongated tubules, granular-, and circular-shaped. Particularly, a subset of neurons exhibited extensively elongated mitochondria. Hyperfusion of mitochondrial network was proposed to be a protective mechanism against Aa-induced cellular stress. It is evident that mitochondria undergo dynamic changes in morphology during neurodegeneration. Taken together, an adaptation model of mitochondrial dynamics in neurodegeneration was proposed. It was speculated that granular mitochondria are triggered as an initial response to increased oxidative stress. With increasing levels of cellular stress, mitochondria undergo hyperfusion to maintain organelle integrity and promote neuronal survival. Mitochondria that do not elongate are prone to organelle fragmentation, which will eventually trigger apoptosis. The current study provides new perspectives of mitochondrial dynamics in neurodegeneration.