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16th World Congress on Targeting Mitochondria | 2025

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

Do our mitochondria run at 50 degrees C?

Left: Mitochondria of human cells illuminated by the thermo-sensitive probe. Four human cells, each with its nucleus (N) and its numerous hot filamentous mitochondria (yellow-red). Right: Mitochondria as radiators. A high-magnification rendering of one such filament reveals parallel arrays of closely juxtaposed membranes that could heat the mitochondrial interior.

Credit: Left: Malgorzata Rak; Right: Terrence G. Frey

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.

News source: www.sciencedaily.com

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

First DNA Sequence from a Single Mitochondria

Manual isolation of a single live mitochondria. The mitochondria can be seen under a microscope where a thin glass tube can be used to isolate the mitochondria from the dendrite region of the mouse neuron. Photo: Jacqueline Morris and Jaehee Lee, Perelman School of Medicine, University of Pennsylvania

DNA sequences between mitochondria within a single cell are vastly different, found researchers in the Perelman School of Medicine at the University of Pennsylvania. This knowledge will help to better illuminate the underlying mechanisms of many disorders that start with accumulated mutations in individual mitochondria and provide clues about how patients might respond to specific therapies.

The findings are published in Cell Reports this week.

Mitochondria, a component of cells that have their own DNA (mtDNA), produce energy for the body, among other functions. One mitochondrion can contain 10 or more different genomes with hundreds to thousands of individual mitochondria residing in each cell. A number of mitochondrial diseases arise from mutations accumulating in mtDNA. For example, these mutations have been found in colorectal, ovarian, breast, bladder, kidney, lung, and pancreatic tumors.

Using methods developed in the lab of senior author James Eberwine, PhD, a professor of Systems Pharmacology and Translational Therapeutics, the investigators extracted single mitochondrion and then extracted its mtDNA. They compared mutations present in single mitochondrion in individual mouse and human neurons and found that mouse cells had more accumulated mutations compared to human cells. Because of this finding that mutations accumulate at a different rate in mice versus humans, Eberwine notes that one important take away from the study is to ensure that mitochondrial diseases or potential therapeutics in cells are examined in models where the mutations parallel those that occur in humans.

The process of mtDNA mutations accruing over a lifetime most likely happens somewhat differently in each person. The study addressed similarities and differences in discrete mtDNA in the same cell and also between cell types such as neurons and astrocytes in the brain.

"By being able to look at a single mitochondrion and compare mutational dynamics between mitochondria, we will be able to gauge the risk for reaching a threshold for diseases associated with increasing numbers of mitochondrial mutations."

For instance, these data may improve diagnosis for neurological diseases, potentially allowing physicians to detect cells that could become diseased or pinpointing patients who may develop certain conditions. This is particularly likely for conditions that more commonly strike the elderly in which mtDNA mutations have been found to accumulate with age.

In the future, the researchers plan to use this knowledge to find ways to slow the rate of mtDNA mutation accumulation in hopes of halting disease progression.

"This roadmap of the location and number of mutations within the DNA of a mitochondrion and across all of a cell's mitochondria is where we need to start," Eberwine said.

News source: www.laboratoryequipment.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.

“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

Unraveling the Mystery of DNA Attacks in Mitochondria Could Pave Way for New Cancer Treatments

Photo source:biosciencetechnology.com

New research has unraveled the mystery of how mitochondria—the energy generators within cells—can withstand attacks on their DNA from rogue molecules.

The findings could pave the way for new treatments to tackle neurodegenerative diseases and cancer. The research could also have important implications for clinical advances in 'mitochondrial donation' -- known as the 'three-parent baby' -- used to correct defects in faulty mitochondria. The five-year study led by scientists at the University of Sheffield, published today (28 April 2017) in Science Advances, reveals how the enzyme TDP1 - which is already known to have a role in repairing damaged DNA in the cell's nucleus - is also responsible for repairing damage to mitochondrial DNA (mtDNA).

Mitochondria are the powerhouses of cells, they generate the energy required for all cellular activity and have their own DNA -- the genetic material which they rely upon to produce important proteins for their function.

During the process of energy production and making proteins, a large amount of rogue reactive oxygen species are produced which constantly attack the DNA in the mitochondria. These attacks break their DNA, however the new findings show mitochondria have their very own repair toolkits which are constantly active to maintain their own DNA integrity.

Lead author of the study, Professor Sherif El-Khamisy, a Wellcome Trust Investigator and Chair of Molecular Medicine at the University of Sheffield, said: "Each mitochondria repair toolkit has unique components -- enzymes -- which can cut, hammer and seal the breaks. The presence of these enzymes is important for energy production.

"Defects in repairing DNA breaks in the mitochondria affect vital organs that rely heavily on energy such as the brain. It also has implications on mitochondria replacement therapies recently approved in the UK and known as 'three parent babies'."

Although much research has focused on how free radicals damage the DNA in the cell's nucleus, their effect on mitochondrial DNA is less well understood despite this damage to mtDNA being responsible for many different types of disease such as neurological disorders.

Having healthy mitochondria is also essential for tissue regeneration, making it particularly important for successful organ transplants. The team further identified a mechanism through which mtDNA can be damaged and then fixed, via a protein called TOP1, which is responsible for untangling coils of mtDNA. When the long strands become tangled, TOP1 breaks and quickly repairs the strands to unravel the knots. If free radicals are also attacking the mitochondrial DNA, then TOP1 proteins can become trapped on the mitochondrial DNA strands, making repair even more difficult. Professor El-Khamisy believes the findings could pave the way for the development of new therapies for mitochondrial disease that boost their DNA repair capacity, or for cancer treatments which could use TDP1 inhibitors to prevent mtDNA repair selectively in cancer cells.

"Cancer relies on cells dividing very quickly. That means they need a lot of energy, so will have really healthy mitochondria," said Professor El-Khamisy.

"If we can find a way to selectively damage the mitochondria in the cancer cells, by preventing or slowing its repair mechanism, this could be really promising."

The findings could also be important for new clinical advances such as the decision by the Human Fertilisation and Embryology Authority (HFEA) to allow 'mitochondrial donation' -- also known as 'three-parent babies' -- where mtDNA from a female donor is introduced to an embryo to correct mitochondrial defects.

"This research suggests that clinicians should assess the function of TDP1 and mitochondrial TOP1 before mitochondrial donation takes place, to ensure the success of this procedure," added Professor El-Khamisy.

"Even if the new embryo has healthy mitochondrial DNA from the donor, it could still have defective TDP1 or mitochondrial TOP1 from the recipient, since they are both produced by the DNA in the cell's nucleus, so mitochondrial DNA damage could still take place over time, and cause disease." Professor Allan Pacey, a fertility expert at the University of Sheffield's Department of Oncology and Metabolism, said "Given that the first UK license to perform mitochondrial donation procedures was awarded by the HFEA last month, the publication of this study is very timely.

"It is important that we know as much as possible about how to identify healthy and defective mitochondria, in order to help those people with debilitating mitochondrial disease."

News source: www.biosciencetechnology.com