Scientists uncover for the first time how the body's energy makers are made using Cryo-Electron Microscopy (cryo-EM) at eBIC within Diamond which is based in Oxfordshire.
A new paper published in Science today (19 February 2021) by an international team of researchers reports an insight into the molecular mechanism of membrane-tethered protein synthesis in mitochondria. This is a fundamental new understanding of how the human mitoribosome functions and could explain how it is affected by mutations and deregulation that lead to disorders such as deafness and diseases including cancer development.
Mitochondria are intracellular organelles which serve as tiny but potent powerhouses in our body. They use oxygen which we inhale and derivatives from food we eat to produce more than 90% of our energy, and therefore effectively support our life. Mitochondria are particularly important in high-energy demanding organs such as heart, liver, muscles and brain. For example, almost 40% of each heart muscle cell is made up of mitochondria.
The bulk of energy production in mitochondria takes place in naturally evolved nano-factories incorporated in specialised membranes. These nano-factories consist of proteins cooperatively transporting ions and electrons to generate the chemical energy currency of our bodies which have to be constantly maintained, replaced and duplicated during cell division. To address this, mitochondria have their own protein making machine called the mitoribosome. The first fundamental understanding of how the mitoribosome looks was achieved in 2014.
"7 years ago, our work on the mitoribosome from yeast was termed the Resolution Revolution. The current study represents an additional advance on the original breakthrough. Not only does it reveal how the human mitoribosome is designed at an unprecedented level of detail, but it also explains the molecular mechanism that drives the process of bioenergetics to fuel life," says lead author, Alexey Amunts, Head of the program for Biology of Molecular Interactions, at SciLifeLab in Sweden.
The term Resolution Revolution was coined at Science magazine in relation to the first successful structure determination of the mitoribosome. This represented a methodological innovation in applying cryo-EM to understand molecular structures. However, this first glimpse into the architecture revealed only a partial picture of a static model. Yet the mitoribosome is a flexible molecular machine that requires the motion of its parts relative to each other in order to work. Therefore, in the current study, the team used the high throughput cryo-EM data acquisition at the electron Bio-Imaging Centre (eBIC) at Diamond to obtain 30 times more data allowing the team to describe conformational changes during the process of protein synthesis and association with the membrane adaptor. eBIC has been a strategic investment from the Wellcome Trust, UKRI's BBSRC and MRC. Being embedded at Diamond, eBIC benefits from amongst other things the well-established user support in place.
"Our study exposed the dynamic molecular mechanism that explains how the mitoribosome actually works to form the cellular powerhouse and reveals that the mitoribosome is much more flexible and active than previously thought. The discovery of intrinsic conformational changes represents a gating mechanism of the mitoribosome without similarity in bacterial and cytosolic systems. Together, the data offer a molecular insight into how proteins are synthesized in human mitochondria," adds Alexey Amunts.
Yuriy Chaban, Principal Electron Microscopy Scientist at eBIC, Diamond comments; "At Diamond, we are pushing the boundaries of what can be measured in the physical and life sciences and this latest development is tribute to the team involved in what can now be routinely achieved.
The most important aspect of Alexey's work is the interaction between mitoribosome and OXA1L and the associated flexibility. The fact that mitoribosome is flexible as such is not novel, but the particular flexibility associated with OXA1L interaction is. This is important for synthesis of membrane proteins, including respiratory chain proteins. Overall, this work significantly widens our understanding how mitoribosome functions. The work by Alexey Amunts lab resolves another mystery about basic biological processes necessary for creating life as we know it."
The sequencing of the human mitochondrial genome 40 years ago was a turning point in mitochondrial research, postulating a putative specialized mechanism for the synthesis of the mitochondrial transmembrane proteins. Indeed, the discovered gating mechanism of the human mitoribosome represents a unique occurrence. Therefore, the structural data offer a fundamental understanding into how bioenergetic proteins are synthesized in our body.
Paper: MITORIBOSOME Mechanism of membrane-tethered mitochondrial protein synthesis - science.sciencemag.org/content/ DOI 10.1126/science.abe0763
Authors/Facilities: Yuzuru Itoh1,2*, Juni Andréll1,2*, Austin Choi3 *, Uwe Richter4,5*, Priyanka Maiti3 , Robert B. Best6 , Antoni Barrientos3 , Brendan J. Battersby4 , Alexey Amunts1,2
Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, , Sweden. 2 Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden. 3 Department of Neurology, University of Miami Miller School of Medicine, Miami, USA. 4 Institute of Biotechnology, University of Helsinki, Finland. 5 Newcastle University, Newcastle upon Tyne, UK. 6 Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, USA.
About eBIC and Diamond Light Source: http://www.diamond.ac.uk
The Electron Bio-Imaging Centre (eBIC) provides scientists with state-of-the-art experimental equipment and expertise in the field of cryo-electron microscopy, for single particle analysis, cryo-tomography and micro-crystal electron diffraction. Currently eBIC houses five Titan Krios microscopes, a Talos Arctica, two Glacios, and a Scios and Aquilos cryo-FIB/SEM; eBIC also houses Leica cryo-CLEM for correlative light and electron microscopy studies.
The location of eBIC adjacent to Diamond beamlines, Central Laser Facility, Research Complex at Harwell and the Rosalind Franklin Institute enables scientists to combine cryo-electron microscopy with many of the other cutting-edge approaches
eBIC was established at Diamond following the award of a £15.6 million grant from the Wellcome Trust, the Medical Research Council (MRC) and the Biotechnology and Biological Sciences Research Council (BBSRC).
Diamond Light Source provides industrial and academic user communities with access to state-of-the-art analytical tools to enable world-changing science. Shaped like a huge ring, it works like a giant microscope, accelerating electrons to near light speeds, to produce a light 10 billion times brighter than the Sun, which is then directed off into 33 laboratories known as beamlines. In addition to these, Diamond offers access to several integrated laboratories including the world-class Electron Bio-imaging Centre (eBIC) and the Electron Physical Science Imaging Centre (ePSIC).
Diamond serves as an agent of change, addressing 21st century challenges such as disease, clean energy, food security and more. Since operations started, more than 14,000 researchers from both academia and industry have used Diamond to conduct experiments, with the support of approximately 700 world-class staff. More than 8,000 scientific articles have been published by our users and scientists.
Funded by the UK Government through the Science and Technology Facilities Council (STFC), and by the Wellcome Trust, Diamond is one of the most advanced scientific facilities in the world, and its pioneering capabilities are helping to keep the UK at the forefront of scientific research.
SciLifeLab. (Science for Life Laboratory) is a collaboration hub for the top research institutions in Sweden, providing the country's largest life sciences infrastructure. It is a joint enterprise of Swedish universities that aims to provide frontline technologies for the academic community and develop cutting-edge research. More information available about Alexey Amunts and his teams work on his webpage https://amuntslab.org/