Mitochondrial network morphology: building an integrative, geometrical view

Abstract

The morphology of mitochondrial networks is complex and highly varied, yet vital to cell function. The first step toward an integrative understanding of how mitochondrial morphology is generated and regulated is to define the interdependent geometrical features and their dynamics that together generate the morphology of a mitochondrial network within a cell. Distinct aspects of the size, shape, position, and dynamics of mitochondrial networks are described and examples of how these features depend on one another discussed.

Figure 1.

Examples of mitochondrial networks at the micron and nanometer scales. (a) Mitochondrial networks can vary from separated structures to interconnected networks. Indian Muntjac deer skin fibroblast (left) and BPAE (bovine pulmonary artery endothelial) cell (right), both expressing a pEYFP-mitochondrial plasmid vector to label mitochondria (yellow-orange). The thin yellow line is an approximate outline of the cell. White arrows point to small boxes indicating either a tubule (left) or tubule branch (right) that are illustrated in (b). (b) Diagram of the organization of the mitochondrial membranes (ultrastructure) at the nanoscale for (i) a tubule and (ii) a tubule branch. Abbreviations in (i) include the outer and inner mitochondrial membrane (OMM and IMM, respectively) and the intermembrane space (IMS). (c) The mitochondrial network in a budding yeast cell. Thin yellow line indicates the outline of the mother (larger, bottom) and bud (smaller, top) compartments. Image is a maximum intensity projection of a three-dimensional z-stack. The size of the cell is approximately the same size as the nuclei in the mammalian cells shown in (a). Images in (a) are reproduced and slightly altered courtesy of and with permission from Michael Davidson (Florida State University) and are featured on the Nikon MicroscopyU website [57].

Figure 2.

Examples of the geometrical features and their dynamics that together generate the overall morphology of mitochondrial networks. Mitochondrial networks in budding yeast are used as a model system to highlight these features but the features are all equally applicable to other organisms and cell types. Mitochondria are labeled by a matrix-targeted fluorescent protein [11] and cell boundaries are shown with thin yellow lines as in Figure 1c. The specific condition or mutation generating each example image is not specified because a variety of mutations can alter each of these geometric features and the purpose of the figure is to illustrate the features themselves in a more general way. Size: example cells with a larger and a smaller mitochondrial network arising from growth in respiratory and non-respiratory conditions, respectively. Shape: example cells with mitochondria lacking their normal underlying tubular structure or exhibiting swollen irregular tubules due to changes in internal membrane organization are shown. Mitochondria in the third cell display normal tubular structure but instead the network contains many fewer branch points than normal. These tubules lie parallel to each other without connections between them. This network is also less uniformly distributed within the cell, highlighting the interdependence between features (depicted by the large gray arrows). Position: example cells with a more uniform versus more asymmetric distribution within the cell. Note the large area of the cell devoid of any mitochondria in the latter case. Dynamics: example cells displaying the resultant over-fragmented and over-fused mitochondrial networks generated when either fusion or fission dynamics are reduced. The final topology of these networks is also greatly altered as a result, once again emphasizing the interdependence of these features. As described in the text, the topology itself may affect the local fission and fusion dynamics as well as the ability of sub-regions of the network to move around within the cell. This may explain the less uniform distribution of the over-fused networks and re-emphasizes the importance of considering both directions of interdependence between features.

Figure 3.

Diagram of the ‘mitochondrial quality control mechanism’ shows three sequential timepoints of fission and fusion. Arrows in Time 1 represent two fission events. Arrow in Time 3 represents the re-fusion of the pink fragment to the network and dissipation of its damage. The red fragment has accumulated too much damage and cannot re-fuse with the network. It will be targeted for mitophagy. Color bar represents the amount of mitochondrial damage.