Principles of the mitochondrial fusion and fission cycle in neurons

Abstract

SummaryMitochondrial fusion-fission dynamics play a crucial role in many important cell processes. These dynamics control mitochondrial morphology, which in turn influences several important mitochondrial properties including mitochondrial bioenergetics and quality control, and they appear to be affected in several neurodegenerative diseases. However, an integrated and quantitative understanding of how fusion-fission dynamics control mitochondrial morphology has not yet been described. Here, we took advantage of modern visualisation techniques to provide a clear explanation of how fusion and fission correlate with mitochondrial length and motility in neurons. Our main findings demonstrate that: (1) the probability of a single mitochondrion splitting is determined by its length; (2) the probability of a single mitochondrion fusing is determined primarily by its motility; (3) the fusion and fission cycle is driven by changes in mitochondrial length and deviations from this cycle serves as a corrective mechanism to avoid extreme mitochondrial length; (4) impaired mitochondrial motility in neurons overexpressing 120Q Htt or Tau suppresses mitochondrial fusion and leads to mitochondrial shortening whereas stimulation of mitochondrial motility by overexpressing Miro-1 restores mitochondrial fusion rates and sizes. Taken together, our results provide a novel insight into the complex crosstalk between different processes involved in mitochondrial dynamics. This knowledge will increase understanding of the dynamic mitochondrial functions in cells and in particular, the pathogenesis of mitochondrial-related neurodegenerative diseases.

HDAC6 inhibition induces mitochondrial fusion, autophagic flux and reduces diffuse mutant huntingtin in striatal neurons

“…We also show that TBA shifts the mitochondrial fission-fusion balance of striatal neurons towards more fusion, possibly because increasing microtubule-dependent movement increases fusion probability [45,46], particularly when mitochondrial contact probability is otherwise reduced by low motility. Inhibition of mitochondrial fission is emerging as a pharmacological strategy to counteract excessive mitochondrial fission in neurodegenerative diseases, such as HD [47,48].…”

Cigarette smoke extract affects mitochondrial function in alveolar epithelial cells

“…As all mitochondrial fusion and fission proteins are present in the cells, we cannot determine which proteins actually are responsible for the observed morphology. However, overexpression of MFN2 in neurons or in pulmonary artery smooth muscle cells induced mitochondrial elongation (8,36); hence, increased fusion and especially increased levels of MFN2 may functionally influence mitochondrial hyperfusion. Thus up- , and 25% CSE; n ϭ 3-6 ϩ SE.…”

Molecular Mechanisms and Physiological Significance of Organelle Interactions and Cooperation

“…Incomplete fission can result in a tangle of interconnected mitochondria and incomplete fusion can result in mitochondrial aggregates, thus motility's effect on the processes seems clear (Chen and Chan, 2009). On the other hand, it has been shown that loss of Miro, which inhibits motility, subsequently inhibits fusion (Cagalinec et al, 2013). It is logical to assume that motility facilitates fission and fusion as at least one mitochondrion must move toward another for fusion to take place and once divided the organelles must move apart to remain separate.…”

“…Additionally, we examined whether or not cluA − mitochondrial morphology is dependent upon these cytoskeletal components and how these components affect motility of the cluA − mitochondria. Finally, due to mounting evidence linking impaired fission and/or fusion to aberrant mitochondrial motility and cellular health (Cagalinec et al, 2013), we assessed the influence of the cytoskeleton on mitochondrial fission and fusion.…”