New target regulating mitochondria during stress
Discovery could lead to new approach to treating heart failure, heart attack, stroke and neurodegeneration
September 19, 2019
Science Daily/Temple University Health System
Like an emergency response team that is called into action to save lives, stress response proteins in the heart are activated during a heart attack to help prevent cell death. As part of this process, Lewis Katz School of Medicine at Temple University researchers show for the first time that one of these specialized emergency responder proteins, known as MCUB, temporarily decreases harmful levels of calcium transport into mitochondria, the energy-generating batteries of cells.
The new research, published online September 19 in the journal Circulation, identifies MCUB as a promising new target for the investigation and treatment of conditions that feature calcium overload and cell death -- conditions that include heart failure, heart attack, stroke, and neurodegeneration.
"MCUB fine-tunes calcium uptake by mitochondria in injured heart tissue, in an attempt to limit calcium overload, which is a major contributor to cell death, particularly following a heart attack," explained John W. Elrod, PhD, Associate Professor in the Center for Translational Medicine at the Temple University Lewis Katz School of Medicine and senior investigator on the new study.
Calcium homeostasis is vital to a number of day-to-day cellular activities and is regulated primarily by mitochondria. For calcium to enter mitochondria, it passes through a channel known as the mitochondrial calcium uniporter (MCU), which resides in the inner mitochondrial membrane where it stimulates the production of ATP, the energy currency of the cell. The amount of calcium that mitochondria take up is regulated by various components of this channel. While MCUB closely resembles the pore forming subunit, MCU, its precise role in calcium regulation is largely unknown, particularly in the context of disease.
Dr. Elrod's team found that deletion of the MCUB gene in cells results in a change in the proteins that make up the calcium channel and that are essential for controlling whether the channel is on or off. Since these alterations are induced by stress, such as heart cell injury, the researchers next investigated the role of MCUB after heart attack in mice. In mice that suffered heart attack, the research team observed significant elevations in MCUB gene expression and decreases in MCU and the gatekeeper of the channel, MICU1. When genetically expressed prior to inducing a heart attack in mice, MCUB altered the channel to reduce calcium overload in the injured heart, ultimately curtailing tissue injury.
Dr. Elrod's team also found that, while it can improve cell survival after heart injury, increased MCUB activity comes at the expense of mitochondrial energy production. "MCUB induction is a compensatory change," explained Dr. Elrod. Just like an emergency responder, MCUB moves in and tries to reduce cell death and aid cell survival -- however, the reduction in mitochondrial calcium uptake is also maladaptive and limits the cell's ability to increase energy during stress.
"MCUB presents us with a new molecular target for investigation," Dr. Elrod said. "It's unique in that it alters the stoichiometry of the channel and thereby presents a new mechanism which may be amendable to therapeutic manipulation. We think that modulating MCUB may allow us to tune down mitochondrial calcium uptake without completely inhibiting all energetic function."
It is hoped that follow-up studies defining the exact sites of molecular interaction will provide additional insight into how to target mitochondrial calcium overload in heart disease.
https://www.sciencedaily.com/releases/2019/09/190919080749.htm
New insight into how obesity, insulin resistance can impair cognition
Science Daily/April 22, 2019
Medical College of Georgia at Augusta University
Obesity can break down our protective blood brain barrier resulting in problems with learning and memory, scientists report.
They knew that chronic activation of the receptor Adora2a on the endothelial cells that line this important barrier in our brain can let factors from the blood enter the brain and affect the function of our neurons.
Now Medical College of Georgia scientists have shown that when they block Adora2a in a model of diet-induced obesity, this important barrier function is maintained.
"We know that obesity and insulin resistance break down the blood brain barrier in humans and animal models, but exactly how has remained a mystery," says Dr. Alexis M. Stranahan, neuroscientist in the MCG Department of Neuroscience and Regenerative Medicine at Augusta University. Stranahan is corresponding author of the study published in The Journal of Neuroscience that provides new insight.
In the brain, adenosine is a neurotransmitter that helps us sleep and helps regulate our blood pressure; in the body it's also a component of the cell fuel adenosine triphosphate, or ATP. Adenosine also activates receptors Adora1a and Adora2a on endothelial cells, which normally supports healthy relationships between brain activity and blood flow.
Problems arise with chronic activation, particularly in the brain, which is what happens with obesity, says Stranahan.
People who have obesity and diabetes have higher rates of cognitive impairment as they age and most of the related structural changes are in the hippocampus, a center of learning and memory and Stranahan's focus of study. Fat is a source of inflammation and there is evidence that reducing chronic inflammation in the brain helps prevent obesity-related memory loss.
In a model that mimics what happens to some of us, young mice fed a high-fat diet got fat within two weeks, and by 16 weeks they had increases in fasting glucose and insulin concentrations, all signs that diabetes is in their future.
In the minute vasculature of the hippocampus, the investigators saw that obesity first increased permeability of the blood brain barrier to tiny molecules like fluorophore sodium fluorescein, or NaFl. Diet-induced insulin resistance heightened that permeability so that a larger molecule, Evans Blue, which has a high affinity for serum albumin, the most abundant protein in blood, also could get through.
When they looked with electron microscopy, they saw a changed landscape. Resulting diabetes promoted shrinkage of the usually tight junctions between endothelial cells and actual holes in those cells. They also saw muscular cells called pericytes that wrap around the exterior of microscopic blood vessels in the brain to give them more strength and help move blood along, start to lose their grip, so blood vessels start to lose their tone and become dysfunctional and inflamed. Pericytes are known to express higher levels of Adora2a than endothelial cells, Stranahan notes. The high-fat diet also promoted swelling of protrusions on astrocytes called end-feet, which also are part of the blood brain barrier. Astrocytes are brain cells that normally nurture neurons, but the pathological state of obesity also altered their form and support.
Angiogenesis, the body's natural attempt to make more blood vessels -- albeit usually dysfunctional, leaky ones -- in response to impaired blood and oxygen flow was happening in the hippocampus by 12 weeks, and upon close inspection, blood vessels were inflamed.
When they gave a drug to temporarily block Adora2a, it also blocked problems with barrier permeability. Whether that could work in humans and long term as a way to avoid cognitive decline in obese humans, remains to be seen, Stranahan notes.
Next they developed a mouse in which they could selectively knock Adora2a out of endothelial cells.
In this transgenic mouse, they turned off Adora2a in the endothelial cells at 12 weeks, and at 16 weeks, when mice should have been exhibiting cognitive impairment and a leaky blood brain barrier, they instead had normal cognition and barrier function and no inflammation.
When they compared the transgenic mice that were on a high- or low-fat diet, they found evidence that the increased permeability of blood vessels in the brain initiates the cycle of inflammation and cognitive impairment.
While it's typically hard to jump from mice to men, the fact that this type of work actually started with human findings likely means that avoiding insulin resistance could potentially halt the increased permeability of the blood brain barrier and decrease in cognitive function, Stranahan says.
"If an individual has already progressed to insulin resistance, these studies underscore the importance of controlling blood sugar levels and avoiding progressing to insulin deficiency (diabetes), which opens the blood brain barrier even further."
The scientists report that the relative accessibility of blood vessels in the brain may also make them a good avenue for preventing obesity's effects on the brain.
It also points to the reality that a variety of drugs given to obese patients may impact their brains to a higher degree, which might be something for patients and their doctors to consider. Stranahan notes that for drugs intended to take action in the brain, such as those for Alzheimer's, that could be a good thing but still needs to be considered. Some commonly prescribed drugs like prednisone, on the other hand, already are really good at getting through and can potentially be bad for the brain, she says.
Next steps in her lab include figuring out where the signal arises that chronically activates Adora2 in fat mice. She suspects it's actually a cascade that includes endothelial cells getting stressed, which increases their metabolism, which means they use more ATP, which can activate Adora2a and set in motion a vicious cycle that eventually takes its toll on the blood brain barrier.
The concept that obesity could affect the blood brain barrier started with people a dozen years ago when Swedish researchers found obese individuals had higher levels of the major antibody immunoglobulin G in their cerebrospinal fluid, when it should have been in their blood. It was an important finding that suggested that obesity and diabetes could enable things to get from the blood to the brain that should not, Stranahan says. Animal studies confirmed it was happening but, again, few studies have looked at why, Stranahan says.
Blood vessels come up from the body and get exceedingly small and fragile as they dive into the brain. While blood vessels that supply areas like our arms and heart are meant to be more porous so they can share plenty of glucose, oxygen and immune cells and other things the body needs, the vasculature in the brain, is supposed to be much more restrictive, letting comparatively little through.
"It's more like a gate than a barrier," says Stranahan, and it's a dynamic barrier at that, based on what the brain is up to. "It's got transporters that can move things across and what is happening in the brain and in the blood can change the way it operates."
She notes that the brain is a huge consumer, sucking up 70 to 80 percent of our oxygen and glucose, but also more fragile than other tissues, super sensitive even to our own immune cells.
"It's like a kid who grows up playing outside in the dirt is going to have a more robust immune system than a kid who grows up staying inside and playing video games," Stranahan says.
Cognitive tests on mice in the study included object recognition and maneuvering a water maze. The scientists looked at other normal functions, like simple motor functions, to see if there were other effects and, at least at those early time points, did not identify others.
https://www.sciencedaily.com/releases/2019/04/190422082253.htm
Intelligence can link to health and aging
May 8, 2019
Science Daily/University of Missouri-Columbia
For over 100 years, scientists have sought to understand what links a person's general intelligence, health and aging. In a new study, a University of Missouri scientist suggests a model where mitochondria, or small energy producing parts of cells, could form the basis of this link. This insight could provide valuable information to researchers studying various genetic and environmental influences and alternative therapies for age-related diseases, such as Alzheimer's disease.
"There are a lot of hypotheses on what this link is, but no model to link them all together," said David Geary, Curators Distinguished Professor of Psychological Sciences in the MU College of Arts and Science. "Mitochondria produce cellular energy in the human body, and energy availability is the lowest common denominator needed for the functioning of all biological systems. My model shows mitochondrial function might help explain the link between general intelligence, health and aging."
Geary's insight came as he was working on a way to better understand gender-specific vulnerabilities related to language and spatial abilities with certain prenatal and other stressors, which may also involve mitochondrial functioning. Mitochondria produce ATP, or cellular energy. They also respond to their environment, so Geary said habits such as regular exercise and a diet with fruits and vegetables, can promote healthy mitochondria.
"These systems are being used over and over again, and eventually their heavy use results in gradual decline," Geary said. "Knowing this, we can help explain the parallel changes in cognition and health associated with aging. Also with good mitochondrial function, the aging processes will occur much more slowly. Mitochondria have been relatively overlooked in the past, but are now considered to relate to psychiatric health and neurological diseases."
Geary said chronic stress can also damage mitochondria that can affect the whole body -- such as the brain and the heart -- simultaneously.
https://www.sciencedaily.com/releases/2019/05/190508134509.htm