Have you heard about moving mitochondria that decide critical cellular functions? Just like people change behaviours based on weather, our body cells can change their shape and organelle positions in response to environmental signals. A research team led by Tamal Das, Associate Professor, Tata Institute of Fundamental Research, Hyderabad, has now uncovered a novel role of mitochondrial position regulating cellular decisions in stiffer tissue environments. 

We are all made of mammalian cells, and every cell has an inner compartment called the nucleus and an outer compartment called the cytoplasm. The nucleus contains genetic material, whereas the cytoplasm contains several organelles such as mitochondria, ribosomes, golgi and many more. The components of both compartments communicate with each other and respond to extracellular cues.

Until now, there has been extensive research into understanding how the extracellular environment could influence cellular architecture. Recently, researchers have focused on understanding how these cues could affect organelle function and, play a crucial role in diseases such as cancer, ageing, and cardiovascular disease. 

This study aimed to unveil how cells and organelles, such as mitochondria, respond to soft and stiff extracellular cues. To understand this difference, researchers grew the MCF‑7 cells, a type of breast cancer cells, on both soft and stiff matrices (a kind of collagen polyacrylamide hydrogels). The lead author Piyush says, ​“In laboratory terms, soft matrix mimics brain tissues, whereas the stiff matrix could be compared to bones.”

Researchers assessed the motility of mitochondria using an automated toolkit called Mitometer, which checks mobility features such as distance and speed. They checked for positions of mitochondria by developing a Matlab code. To visualise, they captured the images of mitochondria using a microscopy technique called time-lapse confocal microscopy for real-time movement within the cells. Using the microscopic images, researchers created a spatial map of the positions of mitochondria inside the cell, keeping the nucleus as the centroid. 

Can we anticipate this magical mystery of mitochondria deciding where it needs to head too?

Surprisingly, the study found that mitochondria clustered near the nucleus and were less networked and less elongated in a stiff matrix than in a soft one. The researchers showed that this process depends on filamin proteins, which are important in cellular adhesion and migration and serve as the primary actin filament cross-linking proteins. Das says, ​“It was not known if the positioning of mitochondria could influence cellular types and their functions. Recently mitochondrial research has gained more interest, especially in cell fate decisions.”

Finally, scientists were curious about the relevance of mitochondrial clustering. It was previously understood that human mesenchymal stem cells, located in the bone marrow, can differentiate into various cell types based on their surroundings. These cells were found to generate bone cells when placed on a stiff matrix. The team found that growing mesenchymal stem cells on a stiff matrix resulted in the clustering of mitochondria around the nucleus and an increased tendency to form bone cells.

Deepa Subramanyam, Professor, National Centre For Cell Science, Pune, who was not associated with the study, says, ​“This very interesting study demonstrates that matrix stiffness alters the intracellular localisation of mitochondria. She adds, 

The study suggests that matrix properties may influence mitochondrial activity and function, which are carefully regulated during normal development, and can be altered in certain diseases.

The study revealed new insights into mitochondria positioning and shapes within cells, influencing cellular identity. Research on mitochondria and matrix is crucial when tissues are impaired due to low stiffness. Ultimately, transferring mitochondria from a healthy cell to affected tissues could help recover tissue functions.