Lee RG, Rudler DL, Raven SA, et al. (2024) Quantitative subcellular reconstruction reveals a lipid mediated inter-organelle biogenesis network. Nature Cell Biology 26: 57–71.

www.nature.com/articles/s41556-023-01297-4

 

To survive, cells rely on collections of organelles, such as mitochondria, endoplasmic reticulum, peroxisomes, Golgi apparatus, and more. Each has specific critical functions. However, they don’t work in isolation. They interact by communicating signals and exchanging materials in an orderly manner. Amazingly, little is known about how they interact.

The laboratory of Aleksandra Filipovska used an innovative strategy to explore the interrelationships of several key organelles with mitochondria. They first established cell lines that lacked genes specific for the production of peroxisomes, Golgi, and ER with mitochondria. Then they combined observations by scanning electron microscopy with multi-omics profiling to examine the RNAs, proteins, lipids, and glycogens that were affected by the perturbations. In this way, they could carefully examine how dysfunction in one organelle affected the mitochondria.

Because mitochondria influence so many cell activities, it wasn’t surprising that the researchers found effects in many systems. However, they found that lipid transfers were the most affected component. This very complete paper documents the many metabolic and morphological interactions within cells and provides insights into how they might be involved in diseases.

Questions for Dr. Filipovska

Congratulations on a tour-de-force paper! Your strategy here seems to be an interesting variation on the systems biology: eliminate one component and see what happens. Has anyone else tried this strategy?

Thank you! This specific strategy of genome-wide screening coupled with FIB-SEM imaging and quantification has not been tried previously, to the best of our knowledge. One of the reasons we decided to pursue this strategy was to get an unbiased account of inter-organelle interactions and changes as opposed to traditional targeted analyses.

Your calculations on the number of genes that might be involved in inter-organelle dysfunctions and diseases large enough to be concerning. How do you read that?  

We were quite surprised to see so many gene changes, and in addition to the genes reported in Lee et al., we have also analyzed many more that are involved in inter-organelle communication and metabolite exchanges. These numbers are starting to make a lot of sense to us now, given how many of these genes are involved in metabolic and biogenesis pathways that are shared across different organelles. For example, the glycerophospholipid pathway spans the endoplasmic reticulum, Golgi apparatus, mitochondria and peroxisomes. Systems biology methods are key to understanding changes across different organelles, providing a larger picture of metabolic processes and common dysfunctions that manifest in different diseases.

You gave a small hint about future experiments to look at tissues under different metabolic demands near the end of the Discussion. Could you expand on that a little?

We are particularly interested in understanding the tissue-specific defects in multi-systemic diseases, such as mitochondrial diseases where a common molecular defect can manifest in different pathologies depending on the affected tissue in a particular disease. This will enable us to design targeted therapeutics for specific organs. Our study also revealed that different molecular defects can cause mitochondrial dysfunction and that targeted treatments of mitochondrial dysfunction may help alleviate symptoms of other diseases that involve mitochondria.

How did you become interested in mitochondria in the first place?

As an undergraduate student, I became fascinated by the bacterial origin of mitochondria and how they retained a level of autonomy within eukaryotic cells, maintaining a very small genome that is essential for life. At the time, very little was known about the regulation of mitochondrial gene expression, despite the many diseases for which there were no cures or treatments that were caused by defects in the mitochondrial genome. I was inspired to understand how the small mitochondrial genome was regulated that could help identify much needed therapies for mitochondrial diseases that are devastating for the patients, often very young infants and children and their families. I started my career trying to modify the mitochondrial genome and find gene therapies, which of course at the time did not work, and the main reason for this was that there was so little known about the mitochondrial genome, transcriptome and proteome. My goal was to focus on understanding the regulation of the mitochondrial genome in my group to help us devise specific therapies for mitochondrial diseases.

 

Reference

Lee RG, Rudler DL, Raven SA, Peng L, Chopin A, Moh ES, McCubbin T, Siira SJ, Fagan SV, DeBono NJ, Stentenbach M, Brown J, Rackham FF, Li J, Simpson KJ, Marcellin E, Packer NH, Reid GE, Padman BS, Rackham O, Filipovska A (2024) Quantitative subcellular reconstruction reveals a lipid mediated inter-organelle biogenesis network. Nature Cell Biology 26: 57–71.

www.nature.com/articles/s41556-023-01297-4