Cells stressed out? Make mitochondria longer
Scientists at The Scripps Research Institute (TSRI) have discovered a new pathway in cells that promotes mitochondrial function during times of stress, a response that can guard against disease as we age.
In response to stress, rather than churn out misshapen proteins, our cells activate protective pathways that take an even more dramatic response -- shutting down protein production entirely. Researchers show that along with this shutdown comes an odd change in shape of organelles called mitochondria, which are responsible for generating cellular energy. Instead of looking like tiny lima beans, mitochondria start to stretch out like noodles.
"Just a couple hours of not making proteins seems to be enough to remodel the mitochondria, and they can stay that way for hours," says Luke Wiseman, PhD, associate professor at TSRI and senior author of the new study, published this week in the journal Cell Reports. "That seems to be a protective way to promote mitochondrial function during the early stages of stress."
The new study offers a closer look at a stress-response pathway in cells called the Unfolded Protein Response (UPR). The UPR has several "branches" that regulate different cellular functions. The Wiseman lab focuses on how stress in a compartment of cells called the endoplasmic reticulum (ER) affects mitochondrial shape and function.
An important player in this response is a sensor/initiator of the UPR called PERK. Wiseman describes the PERK branch as a finely tuned signaling pathway. Without enough PERK signaling, the mitochondria can go haywire in times of stress and significantly challenge cellular function. But if this pathway is hyperactivated, the cell self-destructs.
As we age however, it becomes difficult for the system to maintain this balance. "When you're older, little problems can become bigger problems because the PERK pathway isn't as good at responding," Wiseman says.
Previous research shows that in times of stress, PERK has an important role in regulating many aspects of mitochondrial function including preventing the mitochondrial accumulation of misshapen proteins in response to ER stress. This new study shows that shutting down protein production through activation of PERK also influences mitochondrial shape by increasing its length. Changes in mitochondrial shape are known to influence mitochondrial function, indicating that this is a mechanism to adapt mitochondrial function during ER stress.
The next question for the team was whether this shutdown and remodeling was helping or hurting cells. The mitochondria's main role is to produce energy for the cell, so the researchers measured energy output to see how well mitochondria were functioning after cells experienced ER stress.
They found that shutting down protein production and remodeling the mitochondria did make a difference. "We were able to able to show a protective effect, where mitochondrial energy production was protected due to increased mitochondrial length" says Justine Lebeau, PhD, research associate at TSRI and co-first author of the study.
The researchers suspect that this whole system evolved to give cells a way to respond to stress very quickly, when they just don't have time to make a batch of protective proteins.
"Blocking protein synthesis -- and promoting cellular energy levels by regulating mitochondrial shape -- seems to be an effective way of combatting stress over shorter time scales," says Aparajita Madhavan, graduate student at TSRI and co-first author of the study.
Wiseman thinks defects in PERK sensitivity/activation caused by aging or mutations might hinder this protective regulation of mitochondria. He says defects in PERK signaling are implicated in many diseases that also include mitochondrial dysfunction, such as diabetes, heart disease, and neurodegenerative disorders such as Alzheimer's and Parkinson's disease. He hopes the new work could point to a way to target this aspect of PERK signaling to correct mitochondria defects that cause disease.
News source: https://www.sciencedaily.com/releases/2018/03/180314120214.htm
New Method Improves Delivery of Healthy Mitochondria To Cells Where It Is Dysfunctional, Study Shows
South Korean researchers have developed a simple way to deliver healthy mitochondria to cells where it is dysfunctional, rescuing the cells’ energy levels and metabolic function.
The study, “Delivery of exogenous mitochondria via centrifugation enhances cellular metabolic function,” was published in the journal Scientific Reports.
Defects in mitochondria, the small organelles that are the cell’s powerhouses, contribute to several health problems, including aging, cancer, metabolic disorders and neurodegenerative diseases.
Scientists have developed therapies aimed at rescuing mitochondria’s function. But they are limited to cases where a gene mutation underlies the defects.
Researchers have begun exploring a new strategy — replacing damaged mitochondria with healthy ones.
But a problem scientists have faced is that “mitochondrial transfer methods are inefficient and time-consuming,” the South Korean researchers wrote.
They came up with a new way to deliver healthy mitochondria. The first step is to mix healthy mitochondria with the cells where they need to go. The next step is spinning the mixture — a process called centrifugation — to combine the mitochondria and cells.
The team spun a mixture of mitochondria from human umbilical cord-derived mesenchymal stem cells and cells that needed healthy mitochondria.
They tried the process with more than one type of cell. One experiment involved mixing mitochondria with the same human cells that had donated the mitochondria. Another was mixing human mitochondria with rat muscle cells.
An important finding was that human mitochondria ended up in the rat muscle cells, but rat mitochondria did not increase in the muscle cells. This meant that mitochondria from outside the muscle cells was being successful delivered inside the cells.
When the team compared the efficiency of its mitochondria delivery method with a method called passive transfer, they discovered that their method was much more effective.
“The results from centrifugal transfer indicate that mitochondria can pass through the cell membrane more easily than using the passive transfer approach,” they wrote.
The team maintained the higher efficiency level when they used three other types of cells, including stem cells and cancer cells.
The key finding was that the transferred mitochondria were able to restore lost mitochondrial function, including generating energy and the reactive oxygen species that take part in metabolism.
“This simple and rapid mitochondrial transfer method can be used to treat mitochondrial dysfunction-related diseases,” the team concluded.
News source: https://mitochondrialdiseasenews.com
Photo credit: mitochondrialdiseasenews
Do our mitochondria run at 50 degrees C?
Our body temperature is held at a fairly steady 37.5°C, and the assumption has always been that most of our physiological processes take place at this temperature. The heat needed to maintain this temperature in the face of a colder environment is generated by tiny subcellular structures called mitochondria. But a new study publishing January 25 in the open access journal PLOS Biology by INSERM and CNRS researchers at Hôpital Robert Debré in Paris led by Dr Pierre Rustin (and their international collaborators from Finland, South Korea, Lebanon and Germany) presents surprising evidence that mitochondria can run more than 10°C hotter than the body's bulk temperature, and indeed are optimized to do so. Because of the extraordinary nature of these claims, PLOS Biology has commissioned a cautionary accompanying article by Professor Nick Lane from University College, London, an expert on evolutionary bioenergetics.
To ensure a stable internal temperature, the human body makes use of the heat produced by the last stage of food consumption: combustion of nutrients in structures known as mitochondria, of which there are tens or hundreds in each cell. Mitochondria form a complex network within the cell, and their contents are isolated from the rest of the cell by two membranes. A considerable number of biologically catalyzed chemical reactions take place in their interior; 40% of the energy that they release is captured in the form of a chemical compound, ATP, which is used to drive functions of the body such as heart beats, brain activity or muscle contraction. The remaining 60%, however, is dissipated as heat.
The authors' results appear to show that, in maintaining our body at a constant temperature of 37.5°C, mitochondria operate much like thermostatic radiators in a poorly insulated room, running at a much higher temperature than their surroundings.
This work was made possible by the use of a chemical probe whose fluorescence is particularly sensitive to temperature. When this "molecular thermometer" (Mito Thermo Yellow) was introduced into the heart of the mitochondria, they were able to demonstrate a stabilized temperature of about 50°C. Specifically, the probe's fluorescence suggested that the temperature of the mitochondria in living and intact cells, themselves placed in a culture medium maintained at 38°C, is more than 10°C higher, as long as the mitochondria are functional. This elevated temperature is abolished when the mitochondria are inactivated by various means. The researchers also showed that several human mitochondrial enzymes have evolved an optimum temperature close to 50°C, which helps to support their interpretation of the molecular thermometer data.
Nick Lane, who was not involved in the study, but helped the journal to assess the manuscript, finds the results potentially exciting, but warns that further work needs to be done. In his accompanying Primer, he says "This is a radical claim, and if it is true, how come we didn't know something so important long ago?"
Lane asks a battery of questions about the Mito Thermo Yellow probe, about the plausibility of the extreme temperature gradients which the authors' interpretation imply, and about the meaning of the very concept of "temperature" at such microscopic scales. "We need to know a lot more about both the specific behaviour of Mito Thermo Yellow and its exact location within the mitochondrion before we can come to any firm conclusions about 'temperature'. In the meantime, I doubt that the 10°C temperature difference should be taken literally. But it should be taken seriously."
The authors acknowledge that these high temperatures at the core of the micro-space inside mitochondria are unexpected but emphasize that this revelation should lead to a reassessment of our vision of how mitochondria function and their role in cells. "Much of our knowledge about mitochondria, the activity of their enzymes, the permeability of their membranes, the consequences of genetic defects that impair their activity, the effect of toxins or drugs, have all been established at 37.5°C; the temperature of the human body, certainly, but apparently not that of the mitochondria," they say.
"Heat has fallen out of fashion in biology. Whether or not all these ideas are correct, the distribution and heat generation of mitochondria within cells should be taken much more seriously. These researchers bring this important subject back to centre stage, which is exactly where it should be," concludes Lane.
Journal References:
- Dominique Chrétien, Paule Bénit, Hyung-Ho Ha, Susanne Keipert, Riyad El-Khoury, Young-Tae Chang, Martin Jastroch, Howard T. Jacobs, Pierre Rustin, Malgorzata Rak. Mitochondria are physiologically maintained at close to 50 °C. PLOS Biology, 2018; 16 (1): e2003992 DOI: 10.1371/journal.pbio.2003992
- Nick Lane. Hot mitochondria? PLOS Biology, 2018; 16 (1): e2005113 DOI: 10.1371/journal.pbio.2005113
Mitochondrial Link To Cocaine Addiction Explored
ltered brain energy homeostasis is a key adaptation occurring in the cocaine-addicted brain, but the effect of cocaine on the fundamental source of energy, mitochondria, is unknown. We demonstrate an increase of dynamin-related protein-1 (Drp1), the mitochondrial fission mediator, in nucleus accumbens (NAc) after repeated cocaine exposure and in cocaine-dependent individuals. Mdivi-1, a demonstrated fission inhibitor, blunts cocaine seeking and locomotor sensitization, while blocking c-Fos induction and excitatory input onto dopamine receptor-1 (D1) containing NAc medium spiny neurons (MSNs). Drp1 and fission promoting Drp1 are increased in D1-MSNs, consistent with increased smaller mitochondria in D1-MSN dendrites after repeated cocaine. Knockdown of Drp1 in D1-MSNs blocks drug seeking after cocaine self-administration, while enhancing the fission promoting Drp1 enhances seeking after long-term abstinence from cocaine. We demonstrate a role for altered mitochondrial fission in the NAc, during early cocaine abstinence, suggesting potential therapeutic treatment of disrupting mitochondrial fission in cocaine addiction.
News Source: medicalresearch.com
Alzheimer’s drug turns back clock in powerhouse of cell
Salk researchers identify the molecular target of J147, which is nearing clinical trials to treat Alzheimer’s disease
LA JOLLA—The experimental drug J147 is something of a modern elixir of life; it’s been shown to treat Alzheimer’s disease and reverse aging in mice and is almost ready for clinical trials in humans. Now, Salk scientists have solved the puzzle of what, exactly, J147 does. In a paper published January 7, 2018, in the journal Aging Cell, they report that the drug binds to a protein found in mitochondria, the energy-generating powerhouses of cells. In turn, they showed, it makes aging cells, mice and flies appear more youthful.
Caption: A pipette of J147 from the Schubert lab. Credit: Salk Institute
“This really glues together everything we know about J147 in terms of the link between aging and Alzheimer’s,” says Dave Schubert, head of Salk’s Cellular Neurobiology Laboratory and the senior author on the new paper. “Finding the target of J147 was also absolutely critical in terms of moving forward with clinical trials.”
Schubert’s group developed J147 in 2011, after screening for compounds from plants with an ability to reverse the cellular and molecular signs of aging in the brain. J147 is a modified version of a molecule (curcumin) found in the curry spice turmeric. In the years since, the researchers have shown that the compound reverses memory deficits, potentiates the production of new brain cells, and slows or reverses Alzheimer’s progression in mice. However, they didn’t know how J147 worked at the molecular level.
In the new work, led by Schubert and Salk Research Associate Josh Goldberg, the team used several approaches to home in on what J147 is doing. They identified the molecular target of J147 as a mitochondrial protein called ATP synthase that helps generate ATP—the cell’s energy currency—within mitochondria. They showed that by manipulating its activity, they could protect neuronal cells from multiple toxicities associated with the aging brain. Moreover, ATP synthase has already been shown to control aging in C. elegans worms and flies.
“We know that age is the single greatest contributing factor to Alzheimer’s, so it is not surprising that we found a drug target that’s also been implicated in aging,” says Goldberg, the paper’s first author.
Further experiments revealed that modulating activity of ATP synthase with J147 changes the levels of a number of other molecules—including levels of ATP itself—and leads to healthier, more stable mitochondria throughout aging and in disease.
“I was very surprised when we started doing experiments with how big of an effect we saw,” says Schubert. “We can give this to old mice and it really elicits profound changes to make these mice look younger at a cellular and molecular level.”
The results, the researchers say, are not only encouraging for moving the drug forward as an Alzheimer’s treatment, but also suggest that J147 may be useful in other age-associated diseases as well.
“People have always thought that you need separate drugs for Alzheimer’s, Parkinson’s and stroke” says Schubert. “But it may be that by targeting aging we can treat or slow down many pathological conditions that are old-age-associated.”
The team is already performing additional studies on the molecules that are altered by J147’s effect on the mitochondrial ATP synthase—which could themselves be new drug targets. J147 has completed the FDA-required toxicology testing in animals, and funds are being sought to initiate phase 1 clinical trials in humans.
Other researchers on the study were A. Currais, M. Prior, W. Fischer, C. Chiruta, D. Daugherty, R. Dargusch and P. Maher of the Salk Institute; E. Ratliff and K. Finley of San Diego State University; P.B. Esparza-Molto and J.M. Cuezva of the Universidad Autonoma de Madrid; and M. Petrascheck of The Scripps Research Institute.
The work and the researchers involved were supported by grants from the National Institutes of Health, California Institute of Regenerative Medicine, the Nomis Foundation, the Della Thome Foundation, the Bundy Foundation, the Hewitt Foundation, the Paul F. Glenn Center for Aging Research at the Salk Institute and the Waitt Foundation.
News source: www.salk.edu
