New data sheds light on genesis of our body's powerhouses
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.
News Source: www.sciencedaily.com/
Article source: Yuzuru Itoh, Juni Andréll, Austin Choi, Uwe Richter, Priyanka Maiti, Robert B. Best, Antoni Barrientos, Brendan J. Battersby, Alexey Amunts. Mechanism of membrane-tethered mitochondrial protein synthesis. Science, 2021; 371 (6531): 846 DOI: 10.1126/science.abe0763
Dieting suppresses 'cellular engines', weight loss surgery gives boost to mitochondria
Mitochondria are important cellular power plants whose diminished activity has been previously demonstrated to be associated with obesity by a group of researchers at the University of Helsinki. Now, in a new international study coordinated by the University of Helsinki, the researchers have determined that the method of weight loss affects the metabolic pathways of mitochondria in fat tissue, also known as adipose tissue.
The study was recently published in the Journal of Clinical Endocrinology and Metabolism.
The researchers combined two datasets on calorie restriction diets and two datasets on weight loss surgery, or bariatric surgery, from Europe, monitoring dieters' weight loss as well as metabolism. A biopsy was taken from the study subjects' adipose tissue both at the beginning and the end of their weight reduction.
Ordinary dieting based on calorie restrictions put the mitochondria in the adipose tissue out of tune, further reducing the expression of related genes. In the case of similar weight loss resulting from bariatric surgery, the function of mitochondrial genes was improved and the activity level of mitochondrial metabolic pathways was higher.
The analyses conducted in the study were set in proportion to weight loss so that the results did not depend on greater weight loss in patients who had undergone surgery.
Why does lost weight come back? Impaired mitochondrial function is a potential cause.
Weight loss brings improvements to many metabolic changes associated with obesity, including disorders of glucose and lipid metabolism. Such beneficial effects were also observed in the new study, both in those who followed a regular diet and in those who underwent bariatric surgery.
"This is why it was astonishing to see that the activity of mitochondrial metabolic pathways in adipose tissue was entirely opposite in the two different groups," says researcher Birgitta van der Kolk from the University of Helsinki's Obesity Research Unit.
"Our observations indicate that impaired mitochondrial activity after losing weight by dieting may be the cause of adipose tissue rapidly building up again after weight loss. At the same time, bariatric surgery patients are better protected against regaining weight, which makes us suspect that a recovery of activity by mitochondria in the adipose tissue may be a factor underlying this phenomenon," says Professor Kirsi Pietiläinen, who led the study.
The study utilised a technique known as transcriptomics analysis, which makes it possible to read the genome as a whole.
"By combining these broad-based techniques, biocomputing and extensive European datasets, we observed entirely unexpected links between dieting and the mitochondria of adipose tissue. In the future, it is important to investigate the relevance of these mechanisms to the functioning of such tissue and weight regain," Pietiläinen adds.
News Source: www.sciencedaily.com/
Article source: Birgitta W van der Kolk, Maheswary Muniandy, Dorota Kaminska, Marcus Alvarez, Arthur Ko, Zong Miao, Armand Valsesia, Dominique Langin, Maija Vaittinen, Mirva Pääkkönen, Riikka Jokinen, Sanna Kaye, Sini Heinonen, Kirsi A Virtanen, Daniel P Andersson, Ville Männistö, Wim H Saris, Arne Astrup, Mikael Rydén, Ellen E Blaak, Päivi Pajukanta, Jussi Pihlajamäki, Kirsi H Pietiläinen. Differential Mitochondrial Gene Expression in Adipose Tissue Following Weight Loss Induced by Diet or Bariatric Surgery. The Journal of Clinical Endocrinology & Metabolism, 2021; DOI: 10.1210/clinem/dgab072
Parkinson's, cancer, type 2 diabetes share a key element that drives disease
When cells are stressed, chemical alarms go off, setting in motion a flurry of activity that protects the cell's most important players. During the rush, a protein called Parkin hurries to protect the mitochondria, the power stations that generate energy for the cell. Now Salk researchers have discovered a direct link between a master sensor of cell stress and Parkin itself. The same pathway is also tied to type 2 diabetes and cancer, which could open a new avenue for treating all three diseases.
"Our findings represent the earliest step in Parkin's alarm response that anyone's ever found by a long shot. All the other known biochemical events happen at one hour; we've now found something that happens within five minutes," says Professor Reuben Shaw, director of the NCI-designated Salk Cancer Center and senior author of the new work, detailed in Science Advances on April 7, 2021. "Decoding this major step in the way cells dispose of defective mitochondria has implications for a number of diseases."
Parkin's job is to clear away mitochondria that have been damaged by cellular stress so that new ones can take their place, a process called mitophagy. However, Parkin is mutated in familial Parkinson's disease, making the protein unable to clear away damaged mitochondria. While scientists have known for some time that Parkin somehow senses mitochondrial stress and initiates the process of mitophagy, no one understood exactly how Parkin was first sensing problems with the mitochondria -- Parkin somehow knew to migrate to the mitochondria after mitochondrial damage, but there was no known signal to Parkin until after it arrived there.
Shaw's lab, which is well known for their work in the fields of metabolism and cancer, spent years intensely researching how the cell regulates a more general process of cellular cleaning and recycling called autophagy. About ten years ago, they discovered that an enzyme called AMPK, which is highly sensitive to cellular stress of many kinds, including mitochondrial damage, controls autophagy by activating an enzyme called ULK1.
Following that discovery, Shaw and graduate student Portia Lombardo began searching for autophagy-related proteins directly activated by ULK1. They screened about 50 different proteins, expecting about 10 percent to fit. They were shocked when Parkin topped the list. Biochemical pathways are usually very convoluted, involving up to 50 participants, each activating the next. Finding that a process as important as mitophagy is initiated by only three participants -- first AMPK, then ULK1, then Parkin -- was so surprising that Shaw could scarcely believe it.
To confirm the findings were correct, the team used mass spectrometry to reveal precisely where ULK1 was attaching a phosphate group to Parkin. They found that it landed in a new region other researchers had recently found to be critical for Parkin activation but hadn't known why. A postdoctoral fellow in Shaw's lab, Chien-Min Hung, then did precise biochemical studies to prove each aspect of the timeline and delineated which proteins were doing what, and where. Shaw's research now begins to explain this key first step in Parkin activation, which Shaw hypothesizes may serve as a "heads-up" signal from AMPK down the chain of command through ULK1 to Parkin to go check out the mitochondria after a first wave of incoming damage, and, if necessary, trigger destruction of those mitochondria that are too gravely damaged to regain function.
The findings have wide-ranging implications. AMPK, the central sensor of the cell's metabolism, is itself activated by a tumor suppressor protein called LKB1 that is involved in a number of cancers, as established by Shaw in prior work, and it is activated by a type 2 diabetes drug called metformin. Meanwhile, numerous studies show that diabetes patients taking metformin exhibit lower risks of both cancer and aging comorbidities. Indeed, metformin is currently being pursued as one of the first ever "anti-aging" therapeutics in clinical trials.
"The big takeaway for me is that metabolism and changes in the health of your mitochondria are critical in cancer, they're critical in diabetes, and they're critical in neurodegenerative diseases," says Shaw, who holds the William R. Brody Chair. "Our finding says that a diabetes drug that activates AMPK, which we previously showed can suppress cancer, may also help restore function in patients with neurodegenerative disease. That's because the general mechanisms that underpin the health of the cells in our bodies are way more integrated than anyone could have ever imagined."
News Source: www.sciencedaily.com
Article: Chien-Min Hung, Portia S. Lombardo, Nazma Malik, Sonja N. Brun, Kristina Hellberg, Jeanine L. Van Nostrand, Daniel Garcia, Joshua Baumgart, Ken Diffenderfer, John M. Asara, Reuben J. Shaw. AMPK/ULK1-mediated phosphorylation of Parkin ACT domain mediates an early step in mitophagy. Science Advances, 2021; 7 (15): eabg4544 DOI: 10.1126/sciadv.abg4544
Cells burn more calories after just one bout of moderate aerobic exercise, OSU study finds
In a recent study testing the effects of exercise on overall metabolism, researchers at Oregon State University found that even a single session of moderate aerobic exercise makes a difference in the cells of otherwise sedentary people.
Mitochondria are the part of the cell responsible for the biological process of respiration, which turns fuels such as sugars and fats into energy, so the researchers focused only on mitochondria function.
"What we found is that, regardless of what fuel the mitochondria were using, there were mild increases in the ability to burn off the fuels," said Matt Robinson, lead author on the study and an assistant professor in the College of Public Health and Human Sciences.
OSU researchers recruited participants who do not follow a regular exercise routine and had them ride a stationary bike for an hour at a moderate intensity. They biopsied their muscles 15 minutes later to test how efficient the mitochondria were after the exercise was completed and compared those results with a resting day.
Post-exercise, study participants' mitochondria burned 12-13% more fat-based fuel and 14-17% more sugar-based fuel. While the effects were not drastic, they were consistent, Robinson said.
"It's pretty remarkable that even after just one hour of exercise, these people were able to burn off a little more fuel," he said.
Previous research in the field has long established that regular exercise creates lasting change in people's metabolism, making their bodies burn more energy even when they're not working out.
Prior studies have looked at highly trained or athletic people, but Robinson's team wanted to look specifically at singular bouts of exercise in people who were generally active and disease-free but who did not have structured exercise regimes. These people were on the lower end of fitness, which is associated with low mitochondrial abundance and energy production. Participants were monitored while working out at approximately 65% of their maximal effort, where they could keep up the cycling pace for an hour or more and still comfortably carry on a conversation.
Robinson said they're hoping these results help break down the mental barrier of people thinking they need to be elite athletes for exercise to make an impact on their health.
"From a big picture health perspective, it's very encouraging for people to realize that you can get health benefits from a single session of exercise," Robinson said. "We're trying to encourage people, 'You did one, why don't you try to do two? Let's do three.'
"We know that exercise is good for you, in general. But those benefits of that single bout of exercise seem to fade away after a day or two. You get the long-term benefits when you do that exercise again and again and you make it a regular habit."
In this study, Robinson's research team focused narrowly on mitochondria to find out how big a role mitochondria play in the overall function of muscle metabolism. Other studies are looking at changes in blood flow to the muscle and how the muscle metabolizes fats versus sugars.
From a disease perspective, Robinson said it's clear that obesity and diabetes involve impairments in metabolism. Physiologically, when the body undergoes exercise, sugars tend to be burned off first while fats are stored, but in cases of diabetes and obesity, there is some dysregulation in metabolism that causes the body to not be able to switch between the two types of fuel.
Exercise can help reset that system, he said.
"Since those get burned off in the mitochondria, our hope is that with exercise, we could increase the mitochondria and then improve how the body burns off fats and sugars," he said.
News source: www.sciencedaily.com
Article source: Sean A. Newsom, Harrison D. Stierwalt, Sarah E. Ehrlicher, Matthew M. Robinson. Substrate-specific Respiration of Isolated Skeletal Muscle Mitochondria after 1 h of Moderate Cycling in Sedentary Adults. Medicine & Science in Sports & Exercise, 2021; Publish Ahead of Print DOI: 10.1249/MSS.0000000000002615
Bird blood is a heating system in winter
Credit: Dr. Andreas Nord, researcher in evolutionary ecology at Lund University, Sweden
Researchers at Lund University in Sweden have discovered that bird blood produces more heat in winter, when it is colder, than in autumn. The study is published in The FASEB Journal.
The secret lies in the energy factories of cells, the mitochondria. Mammals have no mitochondria in their red blood cells, but birds do, and according to the research team from Lund and Glasgow this means that the blood can function as a central heating system when it is cold.
"In winter, the mitochondria seem to prioritize producing more heat instead of more energy. The blood becomes a type of radiator that they can turn up when it gets colder," says Andreas Nord, researcher in evolutionary ecology at Lund University who led the study.
Until now, the common perception has been that birds keep warm by shivering with their large pectoral muscles and fluffing up their feathers. Less is known about other heat-regulating processes inside birds.
To investigate the function of mitochondria, the researchers examined great tits, coal tits and blue tits on two different occasions: early autumn and late winter. The researchers took blood samples from the birds and isolated the red blood cells. By using a so-called cell respirometer, a highly sensitive instrument that can measure how much oxygen the mitochondria consume, the researchers were able to calculate how much of the oxygen consumption was spent on producing energy and how much was spent on creating heat. Finally, they also measured the amount of mitochondria in each blood sample.
The results show that the blood samples taken in winter contained more mitochondria and that the mitochondria worked harder. However, the work was not to produce more energy, something the researchers had assumed since birds have a much higher metabolism in winter.
"We had no idea that the birds could regulate their blood as a heating system in this way, so we were surprised," says Andreas Nord.
The researchers will now investigate whether cold weather is the whole explanation for the birds' blood producing more heat in winter. Among other things, they will study whether the food that the birds eat in winter affects the mitochondria.
Dr. Andreas Nord will join the Targeting Mitochondria 2021 Congress and will present his study on Avian red blood cell mitochondria produce more heat in winter than in autumn.News source: www.sciencedaily.com
Article: Andreas Nord, Neil B. Metcalfe, Jennifer L. Page, Anna Huxtable, Dominic J. McCafferty, Neal J. Dawson. Avian red blood cell mitochondria produce more heat in winter than in autumn. The FASEB Journal, 2021; 35 (5) DOI: 10.1096/fj.202100107R
