Mechanisms of Mitochondrial Dynamics

Abstract

Mitochondrial dynamics are a series of different processes that will determine the structure and distribution of this organelle. They include the processes of mitochondrial transport, which allows mitochondria to move along cellular cytoskeleton; fusion and fission processes, which regulate the structure, shape and morphology of these organelles; and the selective degradation or mitophagy, eliminating damaged mitochondria. Moreover, recent studies have described a new mechanism that will also affect mitochondrial distribution: mitochondrial transfer between cells in case of damage or cellular stress. Altogether, these dynamics are essential to allow mitochondria develop their proper function and, consequently, its disruption will be directly related with the initiation or progression of several diseases. Both facts highlight the importance of understanding the underlying mechanisms of mitochondrial dynamics.

Key Concepts

  • The Miro/Trak proteins are the main complex that determines mitochondrial transport and consequently the distribution of mitochondria.
  • Mitochondrial morphology and shape result from the equilibrium between fission and fusion processes.
  • Selective degradation of mitochondria (mitophagy) regulates and it is regulated by mitochondrial transport, fusion and fission.
  • Mitochondria are not limited by cellular boundaries, they can move also between cells in the process called mitochondrial transfer.
  • Deregulation of mitochondrial dynamics will impair normal physiological responses and is directly related to several diseases.
  • Neurons are highly vulnerable to dysfunction in mitochondrial dynamics.

Keywords: mitochondria; fusion; fission; Drp1; Opa1; mitophagy; Miro; Trak; mitofusin

Figure 1. Mitochondrial transport in neurons. (a) Series of images of an axon (green) and its mitochondria (red) along the time. Owing to their thin and long structure, polarised microtubules and the importance for a correct mitochondrial distribution in neurons, axons have been broadly used for the study of mitochondrial transport. In axons, the ‘minus’ end is facing towards the soma and the ‘plus’ end of the microtubules is facing to the axon terminal. Mitochondria that moves during the recorded time are pointed with arrows of different colours. In blue, an example of mitochondria moving retrogradly; in green one moving anterogradly; and in yellow one mitochondria that stops during its movement for a long period of time. Each picture shows mitochondria every 45 s. (b) Scheme of mitochondrial transport mechanisms. In (1) mitochondria moving anterogradly (kinesin‐driven) through microtubule cytoskeleton from the ‘−’ to the ‘+’ end. In (2) scheme shows the mechanism of mitochondrial ‘docking’ in which Syntaphilin (SNPH) arrest mitochondria. In (3), myosin motors transport mitochondria through actin cytoskeleton in the growth cone of the neuron, where microtubules do not arrive.
Figure 2. Mitochondrial fusion and fission. (a) Scheme representing the fusion of two mitochondria. In the initial steps the ‘U’ shape protein mitofusins approach and participate in the fusion of the OMMs. After, the ‘L’ forms of OPA1 (in green) physically interact to fuse the IMMs. (b) Scheme representing the fission of mitochondria. In initial steps, Drp1 (in blue) is translocated from the cytosol to the mitochondria in the places where the mitochondria will divide, in contact with the ER (not shown). Drp1 conform a ring‐shaped complex that will help to divide both membrane. In a final step, Dyn2 (in dark green) helps for the final scission.
Figure 3. PINK1/Parkin dependent mitophagy. Scheme representing the PINK1/Parkin dependent Mitophagy. In basal condition (1), PINK1 is degraded inside the mitochondria (black dots) and Parkin rest as a cytosolic protein. When mitochondria become damaged (2), PINK1 is not degraded and accumulates in the OMM, recruiting and activating Parkin. Then, Parkin will poly‐ubiquitylate several OMM proteins (like miro and mitofusin proteins and consequently affecting mitochondrial dynamics) that will act as a sensor for the recruitment of the autophagosome (3). Eventually, this will lead to the mitochondrial degradation (4).
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Further Reading

Berridge MV, McConnell MJ, Grasso C, et al. (2016) Horizontal transfer of mitochondria between mammalian cells: beyond co‐culture approaches. Current Opinion in Genetics & Development 38: 75–82.

Kraus F and Ryan MT (2017) The constriction and scission machineries involved in mitochondrial fission. Journal of Cell Science 130: 2953–2960.

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Serrat, Roman(Apr 2019) Mechanisms of Mitochondrial Dynamics. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0028274]