Posts tagged mitochondria
Articles and news from the latest research reports.
New clues to causes of peripheral nerve damage
Anyone whose hand or foot has “fallen asleep” has an idea of the numbness and tingling often experienced by people with peripheral nerve damage. The condition also can cause a range of other symptoms, including unrelenting pain, stinging, burning, itching and sensitivity to touch.
Although peripheral neuropathies afflict some 20 million Americans, their underlying causes are not completely understood. Much research has focused on the breakdown of cellular energy factories in nerve cells as a contributing factor.
Now, new research at Washington University School of Medicine in St. Louis points to a more central role in damage to energy factories in other cells: Schwann cells, which grow alongside neurons and enable nerve signals to travel from the spinal cord to the tips of the fingers and toes.
The finding may lead to new therapeutic strategies to more effectively treat symptoms of this highly variable disorder, the scientists report March 6 in the journal Neuron.
“We found that a toxic substance builds up in Schwann cells that have disabled energy factories, leading to the same kind of nerve damage seen in patients with neuropathies,” says senior author Jeffrey Milbrandt, MD, PhD, the James S. McDonnell Professor of Genetics and head of the Department of Genetics. “Now, we’re evaluating whether drugs can block the buildup of that toxin, which could lead to a new treatment for the condition.”
The most common cause of peripheral neuropathy is diabetes, which accounts for about half of all cases. The condition also can occur in cancer patients treated with chemotherapy, which can damage nerves.
In the body, Schwann cells wrap tightly around nerve axons, the fibers that relay nerve signals. Graduate student and first author Andreu Viader and colleagues in Milbrandt’s lab studied Schwann cells in mice with genetically disabled mitochondria, or cellular energy factories. Under normal conditions, these mitochondria produce fuel and intermediates of energy metabolism that allow nerve cells to function.
The researchers showed that the crippled mitochondria activated a stress response in the Schwann cells. Instead of synthesizing fatty acids, a key component of Schwann cells, the cells burned fatty acids for fuel.
Over time, inefficient burning of fatty acids by the crippled mitochondria leads to a build up of acylcarnitines, a toxic substance, in the Schwann cells. The researchers found levels of acylcarnitines up to 100-fold higher in these mutant Schwann cells than in healthy Schwann cells.
And the bad news doesn’t end there. Eventually, the toxin leaks out of the Schwann cells and onto the nerve axons. Studying neurons in petri dishes, the researchers showed that acylcarnitines damage nerve axons and disrupt the ability of nerves to relay signals.
“The toxin leaking out of the Schwann cells and onto the adjacent nerve axons causes damage that results in pain, numbness, tingling and other symptoms,” Milbrandt says. “We think that is a likely mechanism to explain the degeneration of axons that is known to occur in peripheral neuropathies.”
The new research suggests that drugs that inhibit the buildup of acylcarnitines may block axonal degeneration. Milbrandt and his team now are evaluating the drugs in mice with disabled Schwann cells to see if they can slow or alleviate the decay of axons.
Parkin protects from neuronal cell death
Parkinson’s disease is the most common movement disorder and the second most common neurodegenerative disease after Alzheimer’s disease. It is characterized by the loss of dopamin-producing neurons in the substantia nigra, a region in the midbrain, which is implicated in motor control. The typical clinical signs include resting tremor, muscle rigidity, slowness of movements, and impaired balance. In about 10% of cases Parkinson’s disease is caused by mutations in specific genes, one of them is called parkin.
“Parkinson-associated genes are particularly interesting for researchers, since insights into the function and dysfunction of these genes allow conclusions on the pathomechanisms underlying Parkinson’s disease”, says Dr. Konstanze Winklhofer of the Adolf Butenandt Institute at the LMU Munich, who is also affiliated with the German Center for Neurodegenerative Diseases (DZNE). Winklhofer and her colleagues had previously observed that parkin can protect neurons from cell death under various stress conditions. In the course of this project, it became obvious that a loss of parkin function impairs the activity and integrity of mitochondria, which serve as the cellular power stations. In their latest publication, Winklhofer and coworkers uncovered the molecular mechanism that accounts for parkin’s neuroprotective action.
“We discovered a novel signaling pathway that is responsible for the neuroprotective activity of parkin,” Winklhofer reports. The central player of this pathway is a protein called NEMO, which is activated by the enzymatic attachment of a linear chain of ubiquitin molecules. This reaction is promoted by parkin, thereby enabling NEMO to activate a signal cascade, which ultimately leads to the expression of a specific set of genes. Winklhofer’s team identified one essential gene targeted by this pathway, which turned out to code for the mitochondrial protein OPA1. OPA1 maintains the integrity of mitochondria and prevents stress-induced neuronal cell death.
“These findings suggest that strategies to activate this signal pathway or to enhance the synthesis of OPA1 in cells exposed to stress could be of therapeutic benefit,” Winklhofer points out.
The newly identified signal pathway may also be relevant in the context of other neurological conditions that are characterized by the loss of specific neurons. Konstanze Winklhofer and her group are already engaged in further projects designed to determine whether other molecules regulated by this pathway might provide targets for therapeutic interventions.
See-through ‘MitoFish’ opens a new window on brain diseases
Scientists have demonstrated a new way to investigate mechanisms at work in Alzheimer’s and other neurodegenerative diseases, which also could prove useful in the search for effective drugs. For new insights, they turned to the zebrafish, which is transparent in the early stages of its life. The researchers developed a transgenic variety, the “MitoFish,” that enables them to see – within individual neurons of living animals – how brain diseases disturb the transport of mitochondria, the power plants of the cell.
Neurodegenerative diseases such as Alzheimer’s, Parkinson’s, ALS (amyotrophic lateral sclerosis), and MS (multiple sclerosis) are quite different in their effects on patients’ cognitive and motor functions, behavior, and prognosis. Yet on the level of individual neurons, common mechanisms can be observed that either cause or accompany nerve degeneration in a number of different diseases. One of these is a disturbance in the transport of mitochondria, organelles that play several vital roles in the life of a cell — above all, delivering energy where it is needed. And in a neuron, an extremely power-hungry cell, that means moving mitochondria all the way down its longest extension, the axon. Studying mitochondria transport in other animal models of neurodegenerative disease, particularly in mice, has been revealing. But the MitoFish model opens up new possibilities.
The new model was jointly developed in the labs of Prof. Thomas Misgeld of the Technische Universität München (TUM) and Dr. Bettina Schmid, a senior scientist of the German Center for Neurodegenerative Diseases (DZNE) based at the institute of LMU Prof. Christian Haass. “This collaboration has provided a system,” Misgeld says, “with which we can try to understand the traffic rules or the life cycle of a given organelle, in this case mitochondria, in the context of a nerve cell that’s existing in its physiological environment, where it is developing and changing. Most of these things we don’t understand well enough to model them in another setting, so we have the organism do it for us.”
The MitoFish is both readily manipulated, enabling researchers to pose specific questions, and literally transparent — allowing non-invasive in vivo observation of changes relevant to disease processes. It is possible to image a whole, living neuron over time and to follow the movements of mitochondria within it. “The zebrafish is an established genetic model,” Schmid explains, “which means you can bring foreign genes or certain proteins into a fish to test hypotheses about basic biology, disease mechanisms, or potential therapies. And because the early embryo is transparent, you can label specific nerve cells with a fluorescent protein and then look at them in an intact, living animal.”
Scientists create road map to metabolic reprogramming for aging
In efforts to understand what influences life span, cancer and aging, scientists are building road maps to navigate and learn about cells at the molecular level.
To survey previously uncharted territory, a team of researchers at UW-Madison has created an “atlas” that maps more than 1,500 unique landmarks within mitochondria that could provide clues to the metabolic connections between caloric restriction and aging.
The map, as well as the techniques used to create it, could lead to a better understanding of how cell metabolism is rewired in some cancers, age-related diseases and metabolic conditions such as diabetes.
"It’s really a dynamic atlas for regulatory points in mitochondrial function — there are many interesting avenues that other scientists can follow up on," says John Denu, University of Wisconsin-Madison professor of biomolecular chemistry and leader of the epigenetics theme at the Wisconsin Institute for Discovery (WID). "It could take years for researchers to understand what it all means, but at least now we have a list of the most important players."
(Image Credit: © Alexander Raths - Fotolia.com)
Goldilocks was on to something when she preferred everything “just right.” Harvard Medical School researchers have found that when it comes to the length of mitochondria, the power-producing organelles, applying the fairy tale’s mantra is crucial to the health of a cell. More specifically, abnormalities in mitochondrial length promote the development of neurodegenerative diseases such as Alzheimer’s.
"There had been a fair amount of interest in mitochondria in Alzheimer’s and tau-related diseases, but causality was unknown," said Brian DuBoff, first author of the study and a post-doctoral research fellow at Massachusetts General Hospital.
"Ultimately, a deeper understanding of the relationship between mitochondrial function and Alzheimer’s may guide us to develop more targeted therapies in the future," said Mel Feany, HMS professor of pathology at Brigham and Women’s Hospital and senior author of the paper.
The findings were published online in the August 23 issue of Neuron.
'Selfish' DNA in animal mitochondria offers possible tool to study aging
Researchers at Oregon State University have discovered, for the first time in any animal species, a type of “selfish” mitochondrial DNA that is actually hurting the organism and lessening its chance to survive – and bears a strong similarity to some damage done to human cells as they age.
Such selfish mitochondrial DNA has been found before in plants, but not animals. In this case, the discovery was made almost by accident during some genetic research being done on a nematode, Caenorhabditis briggsae – a type of small roundworm.
“We weren’t even looking for this when we found it, at first we thought it must be a laboratory error,” said Dee Denver, an OSU associate professor of zoology. “Selfish DNA is not supposed to be found in animals. But it could turn out to be fairly important as a new genetic model to study the type of mitochondrial decay that is associated with human aging.”