Cells increase their mitochondrial membrane fluidity when made to respire more – Path-Breaking research by UoH and inStem scientists

This work was published recently in the journal Proceedings of National Academy of Sciences (USA), https://www.pnas.org/doi/abs/10.1073/pnas.2213241120.

 

Our body is made up of cells, and all cells require energy. For the cells in our body, a big part of the energy needed is provided by tiny (approximately one millionth of a meter) little cellular compartments (organelles) called mitochondria that are present in most of our body cells. Mitochondria use the body chemicals obtained from breakdown of food, and use these chemicals to make a molecule that is the energy currency of all cells. Mitochondria also control the availability and flow of many important nutrients, minerals and chemicals needed by our body. Problems with mitochondria, including loss of efficiency of energy production at the mitochondria has been directly linked to many of the major diseases that we face, including diabetes, heart disease, Alzheimer’s disease and other neurodegenerative and neurological diseases, blindness etc. This is not surprising because if mitochondria do not function properly, not only is energy production compromised; mitochondria also start releasing harmful chemicals that damage (or kill) our body’s cells.

 

 

Mitochondria has two membranes (layers of lipid molecules). The ‘energy’ production finally happens at the inner membrane (lipid layer) of the mitochondria, using oxygen that we breathe in. This process is called cellular respiration (happens in most cells). For this respiration and ‘energy’ production to occur, there are tiny machines made up of proteins that move electrons and convert oxygen to water. (Electrons are the same charged particles that move when electricity flows through the circuit) The tiny protein machines lining the inner membrane of the mitochondria are described as the electron transport chain; designed by nature to move electrons from one part of the chain to the next, one machine to another and finally to oxygen in a very precise manner. For this chain to work, there are also carrier molecules specially designed to move electrons within the membrane layer from one place to another (one machine to another). How efficiently our cells use and make energy or whether they release harmful biochemicals or not, depends on how well this electron transport chain works and electrons move without leaking.

 

 

Scientists have long been intrigued as to how cells may control the efficiency of this intricate electron chain and energy production. Researches working at University of Hyderabad and Institute of Stem Cell Science and Regenerative medicine (inStem Bangalore) recently discovered that cells may control the working of the energy production, simply by tuning the ‘crowding’ or packing of the inner mitochondrial membrane, the site for ‘energy’ production. Researchers found that when cells are faced with a greater demand for energy, cells appear to reduce the crowding at the mitochondrial inner layer.

 

This work was published recently in the journal Proceedings of National Academy of Sciences (USA), https://www.pnas.org/doi/abs/10.1073/pnas.2213241120. Experimental work was mainly carried out by Dr. Gaurav Singh, a post-doctoral researcher at inStem. The supervision of the work was mainly done by Dr. Akash Gulyani, now a faculty at Department of Biochemistry, School of Life Sciences, University of Hyderabad. Other researchers contributing to the work are Geen George, Dr. K. Ponnuvel Kandaswamy, Dr. Sufi Raja, Dr. Manoj Kumar, Dr. Sunil Laxman and Dr. Shashi Thuttupali.

 

The discovery reported in the paper is significant since packing of this inner layer of mitochondria will speed up or slow down the carrier molecules that carry electrons. More crowded membranes, for example, will mean slower movement of carrier molecules, and maybe less efficient energy production. On the flip side, a less crowded membrane should result in faster transport of carrier molecules and more efficient energy production. Indeed, when faced with increased energy demand, cells reduce crowding! A simple way of thinking about crowding is to think of how movement of molecules will be more in water that flows easily, compared to a viscous oil that does not. This discovery was made possible because researchers were able to precisely measure and even visualize with a microscope the crowding (local viscosity) of the inner layer at every single mitochondrion in a cell. Remember a cell may contain tens and or even hundreds of mitochondria, and with this advance, researchers are now able to get an image of tens of cells in one go, with a precise knowledge of this molecular crowding. Researchers were able to accomplish this by designing and developing an indigenous tool-chest of fluorescent (light emitting) molecules that precisely reports on crowding of molecules at this important layer. These probes molecules were combined with cutting-edge microscopy.

 

 

This discovery helps partly solve a big mystery that had intrigued researchers working on respiration and cellular energy for decades. It may also explain how small changes in the environment of the mitochondria can lead to profound changes in the body, including loss of nerve cell cells seen in dementia. Researchers are now exploring the use of these light emitting fluorescent probes for visualizing stress and damage in cells, and build diagnostic assays for early detection of warning signs of tissue damage and disease. These indigenous probes also may help biotech companies that are working in the area of cell therapy or using cellular assays for drug screening.

 

 

The work was funded by multiple agencies and institutes under auspices of Government of India including Department of Biotechnology, inStem, Institute of Eminence Directorate and School of Life Sciences, University of Hyderabad. The approach of the team is highly interdisciplinary in nature, combining chemistry, imaging and optics, biophysics and biology. Generous support from the Institute of Eminence Directorate, UoH is helping the group of Dr. Akash Gulyani takes this multi-disciplinary approach forward at UoH.

 

Dr. Akash Gulyani can be reached on email: akash.gulyani@uohyd.ac.in