New technique for studying mitochondria could enhance neurodegenerative imaging

Advance offers a new way of investigating diseases – including Alzheimer’s and Parkinson’s – where mitochondria are disrupted.

An advanced imaging-based method from scientists at Scripps Research offers a new way of studying mitochondria, the powerhouses of cells that are responsible for the generation of metabolic energy.

Reporting in the Journal of Cell Biology, the scientists describe a set of techniques that enables the imaging and quantification of even subtle structural changes inside mitochondria, and the correlation of those changes with other processes ongoing in cells.

Longevity.Technology: Mitochondria are involved not only in energy production, but also in several other critical cellular functions, including cell division and cell-preserving responses to various types of stress. Mitochondrial dysfunctions have been observed in a host of diseases including Alzheimer’s, Parkinson’s disease and different cancers, and researchers are obviously eager to develop treatments that can reverse these dysfunctions – but so far, the scientific tools for studying the fine details of mitochondria structure have been limited.

Mitochondria are one of the many membrane-bound molecular machines, or organelles, that dwell within the cells of plants and animals. Typically numbering in the hundreds to thousands per cell, mitochondria have their own small genomes, and have a distinctive structure with an outer membrane and a wavy inner membrane where key biochemical reactions occur. Scientists know that the appearances of mitochondrial structures can change dramatically depending on what function the mitochondrion is performing, or what stresses are present in the cell, and these structural changes can be highly useful markers of cell conditions, although until now, there hasn’t been a good method for detecting and quantifying them.

In the study, Grotjahn’s team put together a computational toolkit to process imaging data from a microscopy technique called cryo-electron tomography (cryo-ET), which essentially images biological samples in three dimensions, using electrons instead of light.

“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,” says study senior author Danielle Grotjahn, PhD, assistant professor in the Department of Integrative Structural and Computational Biology at Scripps Research.

What the researchers have dubbed their “surface morphometrics toolkit” enables the detailed mapping and measurement of the structural elements of individual mitochondria. This includes the bends of the inner membrane and the gaps between membranes – all potentially useful markers of important mitochondrial and cellular events.

“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,” explains Grotjahn lab member Benjamin Barad, PhD, a postdoctoral research associate and co-first author of the study.

The team demonstrated the toolkit by using it to map structural details on mitochondria when their cells are subjected to endoplasmic reticulum stress. ER stress is a type of cell stress that is seen often in neurodegenerative diseases, and the researchers observed that key structural features such as the curvature of the inner membrane, or the minimum distance between inner and outer membranes, changed measurably when under this stress.

With their successful, proof-of-principle demonstrations of the new toolkit, the Grotjahn lab will now use it for studying in more detail how mitochondria respond to cellular stresses or other changes induced by diseases, toxins, infections and even pharmaceuticals.

“We can compare the effects on mitochondria in cells treated with a drug versus the effects on untreated mitochondria, for example,” says Grotjahn lab member and PhD candidate Michaela Medina. Co-first author Medina added: “And this approach is not limited to mitochondria – we can also use it to study other organelles within cells.”