Posts tagged mitochondrial dysfunction
Articles and news from the latest research reports.
How Huntington’s Disease Protein Could Cause Death of Neurons
Scientists at the University of Pittsburgh School of Medicine have identified for the first time a key molecular mechanism by which the abnormal protein found in Huntington’s disease can cause brain cell death. The results of these studies, published today in Nature Neuroscience, could one day lead to ways to prevent the progressive neurological deterioration that characterizes the condition.
Huntington’s disease patients inherit from a parent a gene that contains too many repeats of a certain DNA sequence, which results in the production of an abnormal form of a protein called huntingtin (HTT), explained senior investigator Robert Friedlander, M.D., UPMC Professor of Neurosurgery and Neurobiology and chair, Department of Neurological Surgery, Pitt School of Medicine. But until now, studies have not suggested how HTT could cause disease.
“This study connects the dots for the first time and shows how huntingtin can cause problems for the mitochondria that lead to the death of neurons,” Dr. Friedlander said. “If we can disrupt the pathway, we may be able to identify new treatments for this devastating disease.”
Examination of brain tissue samples from both mice and human patients affected by Huntington’s disease showed that mutant HTT collects in the mitochondria, which are the energy suppliers of the cell. Using several biochemical approaches in follow-up mouse studies, the research team identified the mitochondrial proteins that bind to mutant HTT, noting its particular affinity for TIM23, a protein complex that transports other proteins from the rest of the cell into the mitochondria.
Further investigation revealed that mutant HTT inhibited TIM23’s ability to transport proteins across the mitochondrial membrane, slowing metabolic activity and ultimately triggering cell-suicide pathways. The team also found that mutant HTT-induced mitochondrial dysfunction occurred more often near the synapses, or junctions, of neurons, likely impairing the neuron’s ability to communicate or signal its neighbors.
To verify the findings, the researchers showed that producing more TIM23 could overcome the protein transport deficiency and prevent cell death.
“We learned also that these events occur very early in the disease process, not as the result of some other mutant HTT-induced changes,” Dr. Friedlander said. “This means that if we can find ways to intervene at this point, we may be able to prevent neurological damage.”
The team’s next steps include identifying exact binding sites and agents that can influence the interactions of HTT and TIM23.
(Source: upmc.com)
Scientists find potential target for treating mitochondrial disorders
Mitochondria, long known as “cellular power plants” for their generation of the key energy source adenosine triphosphate (ATP), are essential for proper cellular functions. Mitochondrial defects are often observed in a variety of diseases, including cancer, Alzheimer’s disease, and Parkinson’s disease, and are the hallmarks of a number of genetic mitochondrial disorders whose manifestations range from muscle weakness to organ failure. Despite a fairly strong understanding of the pathology of such genetic mitochondrial disorders, efforts to treat them have been largely ineffective.
But now, graduate student Walter Chen and postdoctoral researcher Kivanc Birsoy, both part of Whitehead Institute Member David Sabatini’s lab, have unraveled how to rescue cells suffering from mitochondrial dysfunction, a finding that may lead to new therapies for this condition.
To find genetic mutations that would rescue the cells, Chen and Birsoy mimicked mitochondrial dysfunction in a haploid genetic system developed by former Whitehead Fellow Thijn Brummelkamp. After suppressing mitochondrial function using the drug antimycin, Chen and Birsoy saw that cells with mutations inactivating the gene ATPIF1 were protected against loss of mitochondrial function.
The protein ATPIF1 is part of a backup system to save starving cells. When cells are deprived of oxygen and sugars, a mitochondrial complex that usually produces ATP, called ATP synthase, switches to consuming it, a state that can be harmful to an already starving cell. ATPIF1 interacts with ATP synthase to shut it down and prevent it from consuming the mitochondrion’s dwindling ATP supply but, in the process, also worsens the mitochondrion’s membrane potential.
“In these diseases of mitochondrial dysfunction, in a sense, it’s a false starvation situation for the cell—there are plenty of nutrients, but because there’s a block in the mitochondria’s normal function, the mitochondria behave as if there’s not enough oxygen,” says Chen, who with Birsoy, authored a paper in the journal Cell Reports describing this work. “So in these situations, activation of ATPIF1 is not good, because there are still many nutrients around to provide ATP. Instead, blocking ATPIF1 is therapeutic because it allows for maintenance of the membrane potential.”
Liver cells are frequently affected in patients with severe mitochondrial disease, so Chen and Birsoy tested the effects of mitochondrial dysfunction in the liver cells of control mice and mice with ATPIF1 genetically knocked out. Again, the liver cells with suppressed ATPIF1 function dealt better with mitochondrial dysfunction than liver cells with normal ATPIF1 activity.
“It’s very simple—if you get rid of ATPIF1, you survive in the presence of mitochondrial dysfunction,” says Birsoy. “From what we see so far, there are no major side effects from blocking ATPIF1 in mice.”
For Chen and Birsoy, the next step in this line of research is to test the effects of ATPIF1 suppression in mouse models of mitochondrial dysfunction. Then they will try to identify therapeutics that effectively block ATPIF1 function.
FDA-approved immune-modulating drug unexpectedly benefits mice with fatal mitochondrial defect
The transplant anti-rejection drug rapamycin showed unexpected benefits in a mouse model of a fatal defect in the energy powerhouses of cells, the mitochondria. Children with the condition, Leigh syndrome, show progressive brain damage, muscle weakness, lack of coordination or muscle control, and weight loss, and usually succumb to respiratory failure.
Leigh syndrome is often diagnosed within the first year of life. Affected children rarely survive beyond 6 or 7 years. At present, the disorder, which can result from several different underlying causes, has no effective treatment.
Reporting this week in Science Express, UW researchers said that they found that treatment with rapamycin “robustly enhances survival and attenuates disease progression in a mouse model of Leigh’s syndrome.” Given as a daily injection, the drug delayed the onset of neurological symptoms, reduced brain inflammation, and prevented brain lesions.
For most of their lives, the treated mice breathed normally, and did not clasp their legs against their bodies, a posture characteristic of this and related brain disorders in mice. Unlike the untreated mice, they could balance and run on a rotarod, a miniature log rolling exercise toy. Both the median and maximum lifespans within the group of treated mice were strikingly extended, the authors noted.
The median lifespan for this mouse condition is 50 days. In comparison, treated males lived a median of 114 days, and females 111 days. The longest survival in the treated group was 269 days, more than triple that of the untreated animals.
“We were excited at the findings because of the potential impact on treatment for kids with this or related mitochondrial diseases,” said the senior author of the study, Dr. Matt Kaeberlein, UW associate professor of pathology. “Similar intervention strategies might also prove useful for a broad range of mitochondrial diseases or for other conditions resulting from mitochondrial dysfunction.”
Mitochondrial defects lessen the amount of energy available to cells. The depletion can damage or destroy vital tissues. Symptoms and severity of illness depends on which types of cells are affected, but in many cases several organ systems operate poorly as a consequence of malfunctioning mitochondria.
Beyond specific mitochondrial diseases, most of them genetic in origin, the decline or dysfunction of mitochondria contribute to many common health problems, including some forms of heart disease, cancer, and muscle, nerve or brain degeneration associated with aging.
Kaeberlein, who researches factors that lengthen life, has been studying the anti-aging effects of rapamycin for several years. The drug, like calorie-restricting diets, acts by inhibiting mTOR, an abbreviation for the eponymously named mechanistic target of rapamycin.
Kaeberlein said, “This study suggests that this drug’s inhibition of mTOR may have a major impact on mitochondria and energy production in cells. We know that rapamycin appears to slow aging. What we don’t know is whether the effects of rapamycin on mitochondria are a major part of the effects of rapamycin on normal aging and aging-related diseases.”
Alongside their work in aging and lifespan in normal mice, Kaeberlein and his lab decided to study rapamycin’s actions on mice with a severe mitochondrial defect. The mouse model for Leigh syndrome was created in the UW laboratory of Dr. Richard Palmiter, a professor of biochemistry and Howard Hughes Medical Institute investigator who was one of the early originators of transgenic mouse models.
The research team included Dr. Philip G. Morgan and Dr. Margaret M. Sedensky, from the Department of Anesthesiology and Pain Medicine at Seattle Children’s Hospital, who study mitochondrial diseases in patients. The lead scientist was Simon C. Johnson from the UW Department of Pathology.
After seeing unexpected benefits on health and survival, the research group looked closely at the effects on metabolism by examining the levels of more than 100 different metabolites – cellular building blocks and intermediates used to make energy – in the treated and untreated Leigh syndrome mice. The team observed that treated mice appear to burn more amino acids and fats as an energy source, rather than the sugar, glucose. This eliminated the accumulation of glucose breakdown byproducts, including lactate. These byproducts can be toxic and are seen at high levels in human Leigh syndrome patients.
“The drug did not substantially alter mitochondrial composition. Instead, the mice appear to bypass the deficiency in their mitochondria through a shift in their metabolic pattern,” Kaeberlein said. “However, we can’t yet explain exactly how this rescues the mice with Leigh syndrome.”
Because this was a mouse study, evidence of efficacy of rapamycin in Leigh syndrome patients will be a necessary next step. Rapamycin already has FDA approval for several uses, including preventing organ transplant rejection and for treating rare forms of cancer; however, the drug also has side-effects which might limit its utility in very young children. Kaeberlein is optimistic, however, that “even if rapamycin doesn’t turn out to be be useful as a treatment for Leigh Syndrome, the lessons learned here will pave the way to new therapies for this devastating disease.”
Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. This deterioration is the primary risk factor for major human pathologies, including cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases. Aging research has experienced an unprecedented advance over recent years, particularly with the discovery that the rate of aging is controlled, at least to some extent, by genetic pathways and biochemical processes conserved in evolution. This Review enumerates nine tentative hallmarks that represent common denominators of aging in different organisms, with special emphasis on mammalian aging. These hallmarks are: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. A major challenge is to dissect the interconnectedness between the candidate hallmarks and their relative contributions to aging, with the final goal of identifying pharmaceutical targets to improve human health during aging, with minimal side effects.
Mutations in VCP gene implicated in a number of neurodegenerative diseases
New research, published in Neuron, gives insight into how single mutations in the VCP gene cause a range of neurological conditions including a form of dementia called Inclusion Body Myopathy, Paget’s Disease of the Bone and Frontotemporal Dementia (IBMPFD), and the motor neuron disease Amyotrophic Lateral Sclerosis (ALS).
Single mutations in one gene rarely cause such different diseases. This study shows that these mutations disrupt energy production in cells shedding new light on the role of VCP in these multiple disorders.
In healthy cells VCP helps remove damaged mitochondria, the energy-producing engines of cells. The mutant protein can’t do this and as a result, the dysfunctional mitochondria build up.
The new study led by Dr Fernando Bartolome, Dr Helene Plun-Favreau and Dr Andrey Abramov of the UCL Institute of Neurology, found that mitochondria are damaged in cells from patients with mutant VCP. Mitochondria generate a cell’s energy, and the study found these damaged mitochondria are less efficient, burning more nutrients but producing less energy. This reduction in available energy makes cells more vulnerable, which could explain why mutations in the VCP gene lead to neurological disorders.
Lead author Dr Fernando Bartolome said, “We have found that VCP mutations are associated with mitochondrial dysfunction. VCP had previously been shown to be important in the removal of damaged mitochondria and proteins, accumulation of which is potentially very toxic to cells. A single mutation in the VCP gene could cause multiple neurological diseases because a different type of protein is accumulating in each disorder”.
In the study, the researchers used live imaging techniques to examine the functioning of mitochondria in patient cells carrying three independent VCP mutations, and in nerve cells in which the amount of VCP has been reduced.
“The next step will be to find small molecules able to correct the mitochondrial dysfunction in the VCP deficient cells”, added Dr Bartolome .
Dr Brian Dickie, the Motor Neuron Disease Association’s Director of Research Development says: “Neurons - and motor neurons in particular - are incredibly energy hungry cells. These new findings from the team at UCL show that there is a significant interruption of energy supply in this hereditary form of MND, which has strong implications for understanding the degenerative process underpinning all forms of the disease.”