New technique for studying mitochondria

Advance offers a new way of investigating diseases—including Alzheimer’s, Parkinson’s and different cancers—where mitochondria are disrupted.

An advanced imaging-based method from scientists at Scripps Research offers a new way of studying mitochondria, which are best known as the “powerhouses” of cells.

In their report on February 14, 2023, in the Journal of Cell Biology, the scientists described 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.

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 eager to develop treatments that can reverse these dysfunctions. But the scientific tools for studying the fine details of mitochondria structure have been limited.

“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.

The co-first authors of the study were Grotjahn lab members Benjamin Barad, PhD, a postdoctoral research associate, and Michaela Medina, a PhD candidate.

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 the mitochondrion is doing, or what stresses are present in the cell. These structural changes therefore can be highly useful markers of cell conditions, though 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. The researchers’
“surface morphometrics toolkit,” as they call it, 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,” Barad says.

The team demonstrated the toolkit by using it to map structural details on mitochondria when their cells are subjected to endoplasmic reticulum stress—a type of cell stress that is seen often in neurodegenerative diseases. They 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,” Medina says. “And this approach is not limited to mitochondria—we can also use it to study other organelles within cells.”

“Quantifying organellar ultrastructure in cryo-electron tomography using a surface morphometrics pipeline,” was co-authored by Benjamin Barad, Michaela Medina, Daniel Fuentes, Luke Wiseman and Danielle Grotjahn, all of Scripps Research.

The research was funded in part by the National Institutes of Health (R01NS095892, RF1NS125674) and the American Cancer Society.

About Scripps Research

Scripps Research is an independent, nonprofit biomedical institute ranked one of the most influential in the world for its impact on innovation by Nature Index. We are advancing human health through profound discoveries that address pressing medical concerns around the globe. Our drug discovery and development division, Calibr, works hand-in-hand with scientists across disciplines to bring new medicines to patients as quickly and efficiently as possible, while teams at Scripps Research Translational Institute harness genomics, digital medicine and cutting-edge informatics to understand individual health and render more effective healthcare. Scripps Research also trains the next generation of leading scientists at our Skaggs Graduate School, consistently named among the top 10 US programs for chemistry and biological sciences. Learn more at www.scripps.edu.

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