New method for studying mitochondria using advanced imaging technology

Scientists at Scripps Research have developed an advanced imaging-based approach that provides a unique perspective on mitochondria, which are best known as the “powerhouses” of cells.

A new toolkit for mapping the mitochondria

A new toolkit for mapping the mitochondria. Video Credit: Scripps Research

The researchers published a study on February 14th, 2023, in the Journal of Cell Biology that outlined a collection of approaches that make it possible to image, quantify, and correlate even minute structural changes inside mitochondria with other cellular processes.

In addition to producing energy, mitochondria are also essential for many cellular processes, including cell division and responses that protect cells from stress.

Researchers are keen to develop treatments that can correct these dysfunctions since it has been found that a variety of disorders, including Alzheimer’s disease, Parkinson’s disease, and several tumors, exhibit mitochondrial dysfunctions. However, there are not many scientific resources available for examining the intricate aspects of the mitochondrial structure.

We now have a powerful new toolkit for detecting and quantifying structural, and thus functional, differences in mitochondria—for example, in diseased versus healthy states.

Danielle Grotjahn, PhD, Study Senior Author and Assistant Professor, Department of Integrative Structural and Computational Biology, Scripps Research

Co-first authors of the study were PhD candidate Michaela Medina and postdoctoral research associate Benjamin Barad from Grotjahn’s lab.

One of the numerous membrane-bound molecular machines, or “organelles,” that occupy the cells of plants and animals is mitochondria. The number of mitochondria per cell typically ranges from hundreds to thousands.

They have their own little genomes and a characteristic shape with an outer membrane and a wavy inner membrane where important metabolic activities happen.

According to how the mitochondrion is performing or what stresses are present in the cell, the appearance of mitochondrial structures can alter significantly. Therefore, despite the lack of an effective method for identifying and measuring them up until now, these structural alterations can be very helpful indicators of cell conditions.

Cryo-electron tomography (cryo-ET), a microscopy method that essentially images biological samples in three dimensions by utilizing electrons instead of light, was used by Grotjahn’s team to analyze imaging data for the study.

The structural components of individual mitochondria can be precisely mapped and measured using what the researchers call a “surface morphometrics toolset.”

This includes the bends in the inner membrane and the spaces between membranes, all of which could serve as effective indicators of significant cellular and mitochondrial activities.

It allows us essentially to turn the beautiful 3-D pictures of mitochondria we can get from cryo-ET into sensitive, quantitative measurements—which we can potentially use to help identify the detailed mechanisms of diseases, for example.

Benjamin Barad, PhD, Postdoctoral Research Associate, Scripps Research

The researchers used the toolkit to map structural information on mitochondria when their cells were subjected to endoplasmic reticulum stress, a type of cell stress that is frequently observed in neurodegenerative diseases.

They discovered that under this stress, important structural elements such as the inner membrane’s curvature and the minimal spacing between the inner and outside membranes underwent significant alteration.

The Grotjahn lab will employ the new toolset for further research into how mitochondria react to cellular stresses or other changes caused by diseases, poisons, infections, and even drugs after successfully demonstrating its functionality in proof-of-principle experiments.

We can compare the effects on mitochondria in cells treated with a drug versus the effects on untreated mitochondria, for example. And this approach is not limited to mitochondria—we can also use it to study other organelles within cells.

Michaela Medin, PhD Student, Scripps Research

Source:
Journal reference:

Barad, B. A., et al. (2023). Quantifying organellar ultrastructure in cryo-electron tomography using a surface morphometrics pipeline. Journal of Cell Biology. doi.org/10.1083/jcb.202204093

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