Live-cell imaging reveals that a functional interaction occurs between two different organelles: contact between the endoplasmic reticulum and mitochondria is needed for mitochondrial DNA replication and division.
The most fundamental difference between prokaryotic and eukaryotic cells is the presence of membrane-bounded organelles in eukaryotic cells. Organelles, such as mitochondria, chloroplasts and the endoplasmic reticulum, allow eukaryotic cells to form microenvironments in which biological processes can be spatially and temporally regulated1. The nuclear genome encodes most organellar proteins, although certain organelles, such as mitochondria and chloroplasts, contain some of their own genetic information. Coordination between the organellar genome and the nuclear genome is therefore required to ensure correct DNA content, DNA replication and protein translation. Writing in Science, Lewis et al.2 investigate whether mitochondrial DNA is replicated at random or at specific locations within the cell, using a live-cell microscope-imaging approach to monitor mitochondrial DNA replication in human cells.
Organelles are enclosed by a lipid bilayer that forms their external boundary. The bilayer is impermeable to most molecules — a prerequisite for the creation of functionally specialized spaces. The fundamental question of how organelles communicate with their external surroundings is still under investigation. The lipid bilayer of each organelle contains transport proteins that can allow the import and export of specific proteins and metabolites. However, cellular communication does not consist solely of soluble signals — cells can also sense their microenvironments through physical and mechanical cues3. This type of sensing might also apply to intracellular organelles, in which case the shape of juxtaposed organellar compartments could potentially affect organelle communication and fundamental biological processes within the cell.
Lewis and colleagues now provide insight into the relationship between organellar structure, the process of mitochondrial DNA synthesis and the transmission of the replicated mitochondrial DNA to daughter mitochondria. Sites where mitochondria are associated with the endoplasmic reticulum (ER) have previously been identified4 in yeast and mammalian cells as locations associated with mitochondrial division. Lewis et al. investigated mitochondrial DNA replication in living human cells using fluorescence microscopy techniques that enabled them to monitor the location of organelles and key intracellular components, including the mitochondrial DNA polymerase protein and a mitochondrial division enzyme. They found a link between the location of replicating nucleoids (the discrete units of mitochondrial DNA within the mitochondria) and the sites of contact between mitochondria and the tubular ER (Fig. 1a).
The authors reasoned that for nucleoids to be distributed equally into daughter mitochondria, nucleoid replication would have to occur at or close to the site of mitochondrial division. They reported that replication occurred close to the point of contact between the mitochondrion and the ER — an association that was originally described in yeast5.
Lewis and colleagues' study provides a leap forward in our understanding by also showing that ER structure impinges on the regulation of mitochondrial DNA homeostasis. The authors manipulated the levels of certain ER proteins to shift the ER structure from a tubular form to a sheet-like form, and they observed by microscopy that the number of nucleoids undergoing DNA replication was reduced, although there were no changes in the total mitochondrial DNA content (Fig. 1b). In our opinion, this work indicates for the first time that the shape of one organelle has a role in determining a key function of a different juxtaposed organelle. Yet, from this study it remains unclear whether the observed effects are directly mediated by a protein complex that connects the ER to the replicating mitochondrial DNA, or whether the effects are mediated indirectly by some unidentified messengers.
The notion that organelle shape can influence function is widespread in biology and is generally appreciated for mitochondria1. However, there has been no previous hint that mitochondrial DNA maintenance and transmission, those key processes for mitochondrial function and cell survival, could be influenced by physical inputs at the interaction interface between mitochondria and the ER. As well as having relevance for mitochondrial diseases, perhaps more importantly, this work raises questions about the role of physical interactions in cross-talk between organelles.
Several questions remain open. For example, it is unclear how shape controls function, and how physical forces might be translated into biological responses. One possibility is that structural changes in the ER might promote remodelling of the cell's protein-filament network, called the cytoskeleton, which might in turn result in the recruitment of specific cellular components such as lipids or proteins to form specialized microdomains on the organelle's surface. Another possibility is that, depending on the sheet-like or tubular structure of the ER, the external forces and physical constraints generated might be sensed locally at the mitochondrion's outer surface to promote activation of a genetic program that affects mitochondrial DNA replication. Analyses of genes that are differentially expressed in association with changes in ER shape might pave the way for studies to determine the mechanisms underlying the relationship between the ER contact and mitochondrial DNA replication.
It is unclear whether tethering molecules might be involved in this process and, if so, which molecules are responsible. Tethers between the ER and mitochondria exist in yeast6 and mammalian7 cells. Proving that mitochondrial DNA replication occurs at sites of organelle tethering would require genetic experiments to delete these tethering structures.
Lewis et al. have extended our understanding of the role of organelle cross-talk to include the control of mitochondrial DNA replication by the ER. Their work opens new avenues of research to explore how one organelle can have a profound influence on a neighbouring one.Footnote 1
Pernas, L. & Scorrano, L. Annu. Rev. Physiol. 78, 505–531 (2015).
Lewis, S. C., Uchiyama, L. F. & Nunnari, J. Science 353, aaf5549 (2016).
Jaalouk, D. E. & Lammerding, J. Nature Rev. Mol. Cell Biol. 10, 63–73 (2009).
Friedman, J. R. et al. Science 334, 358–362 (2011).
Murley, A. et al. eLife 2, e00422 (2013).
Kornmann, B. et al. Science 325, 477–481 (2009).
de Brito, O. M. & Scorrano, L. Nature 456, 605–610 (2008).