Regulation of mitochondrial fusion and division

In many organisms, ranging from yeast to humans, mitochondria fuse and divide to change their morphology in response to a multitude of signals. During the past decade, work using yeast and mammalian cells has identified much of the machinery required for fusion and division, including the dynamin-related GTPases – mitofusins (Fzo1p in yeast) and OPA1 (Mgm1p in yeast) for fusion and Drp1 (Dnm1p) for division. However, the mechanisms by which cells regulate these dynamic processes have remained largely unknown. Recent studies have uncovered regulatory mechanisms that control the activity, assembly, distribution and stability of the key components for mitochondrial fusion and division. In this review, we discuss how mitochondrial dynamics are controlled and how these events are coordinated with cell growth, mitosis, apoptosis and human diseases.

Introduction

Mitochondria acquire specialized shapes, undergo changes in number and intracellular distribution and reorganize their morphology and intricate double-membrane structures dramatically, often in response to the metabolic needs of the cell. A growing body of evidence indicates that mitochondrial fusion and fission have important roles in establishing, maintaining and remodeling mitochondria 1, 2, 3 (Figure 1). The mitochondria of many cell types appear to fuse and divide continuously in a highly regulated manner, such that their overall structure can change rapidly in response to different biological cues. Examples include elongation of mitochondrial tubules during differentiation of embryonic stem cells into cardiomyocytes [4], increased mitochondrial division during synapse formation in hippocampal neurons to recruit mitochondria into the neural protrusions [5] and fragmentation of mitochondria correlating with cytochrome c release during apoptosis 6, 7. Demonstrating the importance of mitochondrial dynamics in human health is the fact that defects in organelle fusion and fission lead to a variety of diseases. For example, mutations in mitochondrial-fusion components are associated with neurodegenerative diseases, such as Charcot-Marie-Tooth (CMT) disease type 2A (CMT2A) and the progressive blindness condition, dominant optic atrophy 1 (DOA1) 8, 9. Similarly, abnormalities in mitochondrial division are associated with CMT type 4A and defects in embryonic and postnatal development, including abnormal brain and retinal development. 10, 11, 12. In the last decade, many studies have identified and characterized proteins responsible for organelle fusion and division 3, 13 and have demonstrated that a balance of these two antagonistic activities controls mitochondrial morphology. Only now are we beginning to gain an appreciation of the molecular mechanisms that regulate these processes. Here, we highlight recent progress made towards understanding the mechanisms that control the frequency and location of mitochondrial fusion and fission.