The “powerhouses” of cells called mitochondria can now be studied in a new way thanks to an innovative imaging-based technique developed by scientists at Scripps Research.
The researchers reported their methods in the Journal of Cell Biology on February 14, 2023. These methods allow for the imaging and quantification of even subtle transformation inside mitochondria, and the linkage of these changes with other processes occurring in cellular environments.
In addition to producing energy, mitochondria are engaged in other vital cellular processes like cell division and survival in the face of diverse stresses. Researchers are keen to create treatments that might cure mitochondrial dysfunctions, which have been reported in a variety of disorders including Alzheimer’s, Parkinson’s, and other malignancies. Yet, until recently, scientific methods for analyzing mitochondria structure were inadequate.
Assistant professor of Integrative Structural and Computational Biology at Scripps Research and senior author of the study Danielle Grotjahn, PhD said that they now have a highly sophisticated toolkit for detecting and quantifying structural, and thus functional, differences in mitochondria—for example, in diseased versus healthy states.
Benjamin Barad, PhD, a postdoctoral research associate in the Grotjahn lab, and Michaela Medina, a PhD candidate in the lab, are the co-first authors of the research.
Mitochondria are a type of membrane-bound molecular machine found inside the cells of plants and animals. Mitochondria are tiny organelles found in every cell that perform essential biochemical operations and have their own small genomes and unique structure, including an outer membrane and a wavy inner membrane. The appearance of mitochondrial structures can undergo dramatic changes, as scientists have discovered, depending on the mitochondrion’s function or the stressors faced by the cell. There hasn’t been a reliable way to identify and quantify these structural alterations, despite their potential utility as markers of cell circumstances.
Cryo-electron tomography (cryo-ET) is a type of microscopy that captures three-dimensional images of biological material by focusing beams of electrons on them rather than light. Grotjahn’s team developed a computer toolbox to interpret imaging data from this method. This surface morphometrics toolset developed by the researchers allows for precise mapping and measuring of individual mitochondrial structures. Inner membrane bends and intermembrane spaces may provide clues to crucial mitochondrial and cellular processes.
According to Barad, this method basically allows them to transfer the beautiful 3-D images of mitochondria they can get through cryo-ET into sensitive, quantitative measures, which might be used to determine the specific causes of illnesses.
This toolset was proved by the group’s ability to map mitochondrial structural features in response to endoplasmic reticulum stress, a form of cellular stress frequently observed in neurodegenerative disorders. They saw measurable changes in core structural elements like the curvature of the inner membrane and the minimum distance between the inner and outside membranes when subjected to this stress.
The Grotjahn lab has shown proof-of-principle for their new toolset and will use it to investigate the mitochrondrial response to cellular stressors such as those caused by pathogens, toxins, and medication.
For instance, as Medina puts it, they may compare the effects on mitochondria in cells treated with a medication to the effects on mitochondria in untreated cells Also, this method is not restricted to studying mitochondria; it can be applied to the investigation of various organelles within cells.
Barad, B. A., Medina, M., Fuentes, D., Wiseman, R. L., & Grotjahn, D. A. (2023). Quantifying organellar ultrastructure in cryo-electron tomography using a surface morphometrics pipeline. The Journal of cell biology, 222 (4), e202204093. https://doi.org/10.1083/jcb.202204093