Aiden Salk, Staff Writer | December 25, 2024
Mitochondria are one of the most unique organelles in a cell. On top of playing a critical role in metabolic energy production in eukaryotic cells, cells that contain a nucleus, they have their own set of DNA separate from the organism’s genome. Overall, the function of a mitochondrion is determined by its structure.
Mitochondria are typically oval or bean-shaped, and they are compartmentalized by a double membrane system with inner and outer membranes. The inner mitochondrial membrane’s folds, called cristae, extend into the interior — or matrix — of the organelle. The inner membrane is the location where most of the energy that comes from the breakdown of sugar and fatty acids is produced. Due to the inner membrane’s protrusion into the matrix, the membrane’s surface area is increased, allowing for more space for energy production to take place. This large surface area is crucial in producing large quantities of energy. However, there are instances where the mitochondria takes on a different shape.
Mitochondria can take on different shapes, such as donut-shaped, elongated, compact, or large in volume. These changes in shape are normal in some cells; for example, in smooth muscle, mitochondria exist as “long filamentous entities, loops and networks,” likely due to high energy demands. On the other hand, certain mitochondrial phenotypes are also correlated with certain diseases or types of diseases. The Hinton Lab at Vanderbilt is currently imaging mitochondria to further understand what shapes are associated with various health outcomes.
Medical diagnoses linked to abnormally shaped mitochondria
There is a correlation between specific mitochondrial shapes and sizes with particular diseases. For instance, having mitochondria that are smaller in volume has been linked to Parkinson’s and Alzheimer’s disease. Interestingly, reduced mitochondrial size with age has also been observed. Enlarged mitochondria have been linked to heart failure. Even larger mitochondria — called megamitochondria — are a sign of mitochondrial swelling that tends to arise when one has either alcoholic or non-alcoholic liver disease. A donut shape is another mitochondrial phenotype that appears in the brain of individuals with cognitive decline. Finally, branched, interconnected networks of mitochondria may be observed in some cancer cells. Knowing some of the diagnoses linked to these mitochondrial phenotypes has helped us begin to understand the effects of their abnormal shape.
The rise of donut-shaped mitochondria and megamitochondria
Donut-shaped mitochondria are correlated with an increase in reactive oxygen species. Reactive oxygen species are formed normally during cellular respiration, the process in which a cell breaks down glucose and stores energy as adenosine triphosphate molecules. Under high metabolic stress, mitochondria take the shape of donuts, particularly in liver cells.
When the body is no longer under metabolic stress, donut-shaped mitochondria have been shown to return to other shapes. This suggests that mitochondria may have changed shape to increase their surface area for energy production under times of metabolic stress. It has also been found that donut-shaped mitochondria may better maintain electrochemical gradients across the inner membrane, which means they can more effectively carry out cellular respiration and produce energy for the body.
Megamitochondria are known to form in response to disease and cellular stressors. The effect of this new phenotype, along with many other abnormal mitochondrial morphologies, are not fully understood. Nonetheless, many phenotypes simply result from abnormal fusion events between two mitochondria. For example, tunnel-shaped mitochondria — called nanotunnels — are theorized to be the result of incomplete fusion events. More specifically, this case of abnormal fusion is a result of mutations in the mitochondrial DNA. Alternatively, donut-shaped mitochondria are also believed to arise from opposite ends of a single mitochondria fusing together, though they do not appear to come from genetic mutations.
Modern mitochondrial imaging techniques
Transmission electron microscopy (TEM) is one of the primary methods used to image mitochondria. TEM is able to produce high-resolution images of organelles by transmitting electrons through a very thin section of a sample and magnifying the results. The results of TEM imaging are in 2D and thus cannot provide information about the 3D dynamics of mitochondria. This makes it difficult to characterize the results of a biopsy through solely looking at the mitochondrial shape under an electron microscope.
At Vanderbilt, the Hinton Lab works to reconstruct 3D images of mitochondria via computer analysis. 3D mitochondria reconstruction will be helpful in hypothesizing the effects of different mitochondrial phenotypes. They may also be able to look at the differential shapes of the infoldings of the mitochondrial membrane as well, which will aid in our understanding of the effects of various mitochondrial phenotypes.
Overall, as new technologies progress, cheaper imaging techniques will be available. Unfortunately, regular monitoring of one’s mitochondria shapes is still costly and would be troublesome to do on a large scale. However, the development of new 3D rendering techniques certainly brings promising implications for developing treatments and understanding cellular dynamics in terms of mitochondria.
References
Cooper, G. M. (2000, July 15). Mitochondria. The Cell: A Molecular Approach. 2nd edition. https://www.ncbi.nlm.nih.gov/books/NBK9896/
Hinton, A., Claypool, S. M., Neikirk, K., Senoo, N., Wanjalla, C. N., Kirabo, A., & Williams, C. R. (2024). Mitochondrial structure and function in human heart failure. Circulation Research, 135(2), 372–396. https://doi.org/10.1161/circresaha.124.323800
Jenkins, B. C., Neikirk, K., Katti, P., Claypool, S. M., Kirabo, A., McReynolds, M. R., & Hinton, A. (2024). Mitochondria in disease: Changes in shapes and Dynamics. Trends in Biochemical Sciences, 49(4), 346–360. https://doi.org/10.1016/j.tibs.2024.01.011
Lam, J., Katti, P., Biete, M., Mungai, M., AshShareef, S., Neikirk, K., Garza Lopez, E., Vue, Z., Christensen, T. A., Beasley, H. K., Rodman, T. A., Murray, S. A., Salisbury, J. L., Glancy, B., Shao, J., Pereira, R. O., Abel, E. D., & Hinton, A. (2021, August 24). A universal approach to analyzing transmission electron microscopy with imagej. Cells. https://pmc.ncbi.nlm.nih.gov/articles/PMC8465115/
McCarron, J. G., Wilson, C., Sandison, M. E., Olson, M. L., Girkin, J. M., Saunter, C., & Chalmers, S. (2013). From structure to function: Mitochondrial morphology, motion and shaping in vascular smooth muscle. Journal of Vascular Research, 50(5), 357–371. https://doi.org/10.1159/000353883
Picca, A., Faitg, J., Auwerx, J., Ferrucci, L., & D’Amico, D. (2023, November 30). Mitophagy in human health, ageing and disease. Nature News. https://www.nature.com/articles/s42255-023-00930-8#:~:text=Mitophagy%20is%20a%20specific%20form,support%20developmental%20processes5%2C6.
Vanderbilt University. (1970, June 11). Hinton Lab – Home. Vanderbilt University. https://lab.vanderbilt.edu/hinton-lab/
Vanderbilt University. (1970, June 14). Research. Hinton Lab – Research. https://lab.vanderbilt.edu/hinton-lab/research/
