Scientists discover for the first time how the body's energy generators are made using cryo-electron microscopy (cryo-EM) at the eBIC in Diamond, Oxfordshire.
A new paper published in science Today (February 19, 2021) an international team of researchers reported an insight into the molecular mechanism of membrane-bound protein synthesis in mitochondria. This is a fundamental new understanding of how the human mitoribosome works and could explain how it is affected by mutations and deregulation that lead to disorders such as deafness and diseases including cancer.
Mitochondria are intracellular organelles that serve as tiny but powerful powerhouses in our bodies. They use oxygen that we breathe and derivatives from the foods we eat to produce more than 90% of our energy and thus effectively support our lives. Mitochondria are especially important in high-energy organs such as the heart, liver, muscles, and brain. For example, almost 40% of every heart muscle cell is made up of mitochondria.
Most of the energy generation in mitochondria takes place in naturally developed nanofactories that are built into specialized membranes. These nanofactories are made up of proteins that cooperatively transport ions and electrons to create our body's chemical energy currency, which must be constantly maintained, replaced, and duplicated as cells divide. To remedy this, mitochondria have their own protein making machine called the mitoribosome. The first basic understanding of what the mitoribosome looks like was achieved in 2014.
"7 years ago, our work on the yeast mitoribosome was referred to as the Resolution Revolution. The current study represents an additional advance on the original breakthrough. It not only shows how the human mitoribosome is constructed in an unprecedented level of detail, but also explains that molecular mechanism that drives the process of bioenergetics to 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 on the first successful structure determination of the mitoribosome. This was a methodological innovation in the application of cryo-EM to understand molecular structures. However, this first insight into the architecture only yielded a partial image of a static model. However, the mitoribosome is a flexible molecular machine that requires its parts to move relative to one another in order to work. Therefore, in the current study, the team used high-throughput cryo EM data acquisition at Diamond's Electron Bio-Imaging Center (eBIC) to obtain 30 times more data that the team used to conformational changes during the process of protein synthesis and imaging. description could describe association with the membrane adapter. eBIC was a strategic investment by the Wellcome Trust, the BBSRC and the MRC of UKRI. EBIC is embedded in Diamond and benefits, among other things, from the established user support.
"Our study revealed the dynamic molecular mechanism that explains how the mitoribosome actually forms the cellular powerhouse, and shows 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 with no resemblance In bacterial and cytosolic systems, the data together offer a molecular insight into the synthesis of proteins 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 natural and life sciences, and this latest development pays 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 flexibility that goes with it. The fact that mitoribosome is flexible as such is not new, but the particular flexibility associated with the OXA1L interaction is. This is important for the synthesis of membrane proteins, including respiratory chain proteins. Overall, this work greatly expands our understanding of how mitoribosomes work. The work of Alexey Amunt's laboratory solves another mystery about the basic biological processes necessary to create life as we know it. "
The sequencing of the human mitochondrial genome 40 years ago marked a turning point in mitochondrial research and postulated a putative specialized mechanism for the synthesis of mitochondrial transmembrane proteins. Indeed, the gating mechanism discovered in the human mitoribosome is a unique event. Therefore, the structural data provide a basic understanding of how bioenergetic proteins are synthesized in our body.