Scientists have long recognized that organelles within cells have evolved specific shapes and sizes tailored to their functions. Now, researchers from Johns Hopkins have devised a bacteria-based method to examine whether form indeed follows function, potentially offering therapeutic applications. This tool accurately targets and disassembles the outer membranes of organelles, and it’s accessible to other scientists for research. Intriguingly, it might also disrupt aggregated proteins linked to neurodegenerative diseases like ALS. The Johns Hopkins team primarily studied mitochondria, the cell’s energy generators, Golgi bodies responsible for protein processing and packaging, and the nucleus, the cell’s command center. Their findings are detailed in Cell Reports.
“We’ve created a scientific instrument to investigate the relationship between organelle appearance and function,” explains Dr. Takanari Inoue, a cell biology professor at Johns Hopkins University School of Medicine. This tool could shed light on how altering organelle shapes can impact their functions, either positively or negatively.
In the case of mitochondria, for instance, individuals with Alzheimer’s disease experience an enlargement and disorganization of these organelles inside their cells, as explained by Inoue. Conversely, those with progeria, a condition associated with accelerated aging, exhibit misshapen nuclei.
To develop their innovative tool, Hideki Nakamura, a postdoctoral researcher in Inoue’s lab, turned to Listeria bacteria, notorious for causing foodborne illnesses. Listeria, when invading animal cells, harness the cell’s actin protein stores to move around, gather nutrients, and eventually escape to infect other cells.
Collaborating with physicists skilled in measuring the physical forces generated by Listeria’s manipulation of actin, Nakamura engineered Listeria to assemble proteins and molecules that interact with organelle surfaces within a cell. This interaction applies force to the organelle’s surface, ultimately breaking it open.
While existing techniques can rupture organelles within cells, such as optical tweezers or cell stretching, these methods approach the cell from the outside. None of them can precisely target organelles from within the cell.
Nakamura, now at Kyoto University, Inoue, and their team named their groundbreaking tool “ActuAtor.”
In their series of experiments, the Johns Hopkins researchers tested ActuAtor on human epithelial cells, which line various organs and skin surfaces. Remarkably, they succeeded in completely fragmenting mitochondria within these cells only 10 minutes after introducing ActuAtor.
Analyzing mitochondrial function before and after altering their shape, they discovered no significant differences in power generation. However, the cells did exhibit a response to the altered mitochondrial shape by increasing efforts to eliminate these misshapen organelles, albeit to a minor extent.
“In this instance, our team concluded that function may not necessarily correlate with form in mitochondria,” notes Inoue.
The team also conducted tests on brain cells and various organelles, including nuclei and Golgi bodies, successfully using ActuAtor to disrupt these organelles.
Furthermore, Inoue and Nakamura adapted ActuAtor to disperse protein granules that accumulate within cells due to environmental stressors, such as temperature changes or oxygen deprivation. They plan to explore the tool’s potential in dispersing protein aggregates that form in brain cells, offering hope for treating neurodegenerative conditions like ALS.