neurosciencestuff
neurosciencestuff:

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.

neurosciencestuff:

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.

sciencenote
sciencenote:

First direct evidence of cosmic inflation
Almost 14 billion years ago, the universe we inhabit burst into existence in an extraordinary event that initiated the Big Bang. In the first fleeting fraction of a second, the universe expanded exponentially, stretching far beyond the view of our best telescopes. All this, of course, was just theory.
"Detecting this signal is one of the most important goals in cosmology today. A lot of work by a lot of people has led up to this point," said John Kovac (Harvard-Smithsonian Center for Astrophysics), leader of the BICEP2 collaboration.
These groundbreaking results came from observations by the BICEP2 telescope of the cosmic microwave background — a faint glow left over from the Big Bang. Tiny fluctuations in this afterglow provide clues to conditions in the early universe. For example, small differences in temperature across the sky show where parts of the universe were denser, eventually condensing into galaxies and galactic clusters.
Since the cosmic microwave background is a form of light, it exhibits all the properties of light, including polarization. On Earth, sunlight is scattered by the atmosphere and becomes polarized, which is why polarized sunglasses help reduce glare. In space, the cosmic microwave background was scattered by atoms and electrons and became polarized too.
"Our team hunted for a special type of polarization called ‘B-modes,’ which represents a twisting or ‘curl’ pattern in the polarized orientations of the ancient light," said co-leader Jamie Bock (Caltech/JPL).
(…)

sciencenote:

First direct evidence of cosmic inflation

Almost 14 billion years ago, the universe we inhabit burst into existence in an extraordinary event that initiated the Big Bang. In the first fleeting fraction of a second, the universe expanded exponentially, stretching far beyond the view of our best telescopes. All this, of course, was just theory.

"Detecting this signal is one of the most important goals in cosmology today. A lot of work by a lot of people has led up to this point," said John Kovac (Harvard-Smithsonian Center for Astrophysics), leader of the BICEP2 collaboration.

These groundbreaking results came from observations by the BICEP2 telescope of the cosmic microwave background — a faint glow left over from the Big Bang. Tiny fluctuations in this afterglow provide clues to conditions in the early universe. For example, small differences in temperature across the sky show where parts of the universe were denser, eventually condensing into galaxies and galactic clusters.

Since the cosmic microwave background is a form of light, it exhibits all the properties of light, including polarization. On Earth, sunlight is scattered by the atmosphere and becomes polarized, which is why polarized sunglasses help reduce glare. In space, the cosmic microwave background was scattered by atoms and electrons and became polarized too.

"Our team hunted for a special type of polarization called ‘B-modes,’ which represents a twisting or ‘curl’ pattern in the polarized orientations of the ancient light," said co-leader Jamie Bock (Caltech/JPL).

(…)