Abstract
Mitochondria are highly dynamic organelles undergoing coordinated cycles of fission and fusion, referred as ‘mitochondrial dynamics’, in order to maintain their shape, distribution and size. Their transient and rapid morphological adaptations are crucial for many cellular processes such as cell cycle, immunity, apoptosis and mitochondrial quality control. Mutations in the core machinery components and defects in mitochondrial dynamics have been associated with numerous human diseases. These dynamic transitions are mainly ensured by large GTPases belonging to the Dynamin family. Mitochondrial fission is a multi-step process allowing the division of one mitochondrion in two daughter mitochondria. It is regulated by the recruitment of the GTPase Dynamin-related protein 1 (Drp1) by adaptors at actin- and endoplasmic reticulum-mediated mitochondrial constriction sites. Drp1 oligomerization followed by mitochondrial constriction leads to the recruitment of Dynamin 2 to terminate membrane scission. Inner mitochondrial membrane constriction has been proposed to be an independent process regulated by calcium influx. Mitochondrial fusion is driven by a two-step process with the outer mitochondrial membrane fusion mediated by mitofusins 1 and 2 followed by inner membrane fusion, mediated by optic atrophy 1. In addition to the role of membrane lipid composition, several members of the machinery can undergo post-translational modifications modulating these processes. Understanding the molecular mechanisms controlling mitochondrial dynamics is crucial to decipher how mitochondrial shape meets the function and to increase the knowledge on the molecular basis of diseases associated with morphology defects. This article will describe an overview of the molecular mechanisms that govern mitochondrial fission and fusion in mammals.
Highlights
For a long time, mitochondria have primarily been considered as the ‘powerhouse’ of the cell, producing the energy required for cell metabolism by oxidative phosphorylation (OXPHOS) [1,2]
Mitochondrial fusion and fission are crucial events and it is evident that these dynamic morphological transitions control cell fate decisions
The discovery of new players which regulate these events is in constant evolution, from unexpected organelles [190] to key biological events [191], and that will continue in the following years with the development of novel microscopy technology and genetic tools
Summary
Mitochondria have primarily been considered as the ‘powerhouse’ of the cell, producing the energy required for cell metabolism by oxidative phosphorylation (OXPHOS) [1,2]. Drp binds directly PA, via an unstructured loop in its stalk domain, at the OMM constriction sites leading to its oligomerization but to an inhibition of its GTPase activity, which results in mitochondrial hyperfusion [130,131] Overall, these studies highlight the antagonistic roles of PA and CL microdomain formation in mitochondrial fission and fusion regulation. Pathogenic mutations in genes encoding the core fission and fusion machinery components have been linked to different severe human disorders, highlighting the physiological role of mitochondrial dynamics in cell homoeostasis c 2018 The Author(s) The clinical and genetic complexity of these disorders have not been explained yet and additional studies are required to improve our understanding on the molecular basis of diseases associated with mitochondrial dynamic defects
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