Mitochondrial Metabolism Dictates Neurons’ Growth Rate

reposted from Mitochondrial Metabolism Dictates Neurons’ Growth Rate Altering the rate of respiration in mitochondria changes how fast neurons grow, making mouse neurons grow more like human ones and vice versa, a study finds. a human neuron illuminated in bright green on a black background. A black and white headshot of Katherine Irving Katherine Irving Jan 30, 2023 | 4 min read PDF VERSION ABOVE: A human cortical neuron RYOHEI IWATA Human brains grow extraordinarily slowly—a trait many neuroscientists speculate is related to our distinctive intellect. But how and why a human neuron takes years to grow when a mouse neuron grows for mere weeks has remained unclear. Now, scientists have uncovered one piece of the puzzle: Neuron growth is mediated by its mitochondria’s metabolism, according to a January 26 study in Science. The finding could not only help answer fundamental questions about brain development, the study authors say it could widen treatment options for developmental disorders. “This is the most exciting study I’ve read in a while,” says Suzana Herculano-Houzel, a biologist and neuroscientist at Vanderbilt University who wasn’t involved in the research. “It opens a path for finding answers to, what is to me, one of the biggest questions we have: What makes different brains different?” For senior study author and developmental biologist Pierre Vanderhaeghen, the underlying cause of human neurons’ prolonged growth had long lay tantalizingly out of reach. Nearly a decade ago, he and colleagues at the Free University of Brussels in Belgium put human cortical neurons inside mouse brains, expecting them to grow faster. But to their surprise, the human neurons still grew slowly when transplanted. This suggested to Vanderhaeghen, who also works at the Flanders Institute for Biotechnology and the Catholic University of Leuven, that the cause of a neuron’s glacial growth was intrinsic to the neuron itself and not the consequence of signals from the surrounding brain, he explains. Moreover, he and his colleagues at the time noted that every single aspect of the neuron, from its dendrites to its synapses to its axon, grows in synchrony, indicating that the growth is regulated by a ubiquitous, basal component of the cell. Other research had posited that mitochondria may somehow play important roles in the development of cells. So he and his team set out to investigate whether mitochondria are involved in regulating neuron growth. A purple human neuron with white mitochondria dotting the surface A human neuron with mitochondria stained in white RYOHEI IWATA First, though, they needed to ensure they could accurately pinpoint the age of any given neuron. Knowing a neuron’s age is vital for gauging its growth over time, but getting an exact birthdate for each neuron had been next to impossible, Vanderhaeghen explains, as neurons don’t develop at the same rate as one another, even when their original stem cells are created at the same time. However, stem cells can only become neurons after promoter NeuroD1 is activated. So Vanderhaeghen and colleagues came up with a genetic tool that uses an engineered recombinase enzyme called CreER that identifies when NeuroD1 is turned on and immediately tags the neuron—essentially flagging its “birth.” With the ability to date the neurons, Vanderhaeghen and his team could start testing the effect mitochondria have on neuron growth rates. Initially, Vanderhaeghen says, the team examined mitochondrial morphology and genetics. But on a whim, they also decided to look at the organelles’ respiration rates—basically, how much oxygen they consume, which is also a measure of how much cellular fuel they produce. They used oxygraphy to monitor the oxygen intake of mouse neurons for the first 20 days after their birth—and were stunned to find that after two weeks, the oxygen consumption rate of neurons had grown to nearly ten times that of human neurons. From there, Vanderhaeghen says everything fell into place. The team knew they could manipulate mitochondrial respiration pharmacologically, so they sped up metabolism in human cortical neurons in vitro. Vanderhaeghen recalls a moment in the lab looking at the neurons; at only a few weeks old, the accelerated cortical neurons were considerably more mature than a normal human neuron. “To us, this was a big eureka moment,” he says. “There we thought, ‘this is it.’” The scientists tested the same principle in vivo, speeding up the mitochondrial metabolism of human neurons and implanting them into mice, as well as slowing down the mitochondrial metabolism of mouse neurons both in culture and inside the mice’s brains. The results from both in and out of the brain aligned: Human neurons with increased metabolic rates grew faster than normal, and mouse neurons with decreased mitochondrial metabolic rates displayed slower growth. Many scientists theorize that the human brain’s slow growth is part of what allows for our unique mental capacities. Knowing that a metabolism regulator can slow or speed up that growth will allow for further studies into what makes us human, Vanderhaeghen posits. He adds that targeting mitochondrial metabolism could one day be considered in the treatment of some developmental disorders, which can arise from brain development that is either too fast or too slow. However, he emphasizes that this study is only the beginning. “I would be very naive to think that mitochondria are the [only] solution” to resolving issues related to developmental timing, he says. “Mitochondria are just one mechanism, and there are probably going to be many others.” Nonetheless, Herculano-Houzel is excited to see where this research will go. “That is the definition of good science: You answer one question, and that brings up ten new questions you didn’t know you had,” she says. “What happens if you play with energy transfer in a developing brain? Do you directly affect the size of the brain? Do you affect how many neurons are generated? These are all fundamental questions, and they can all be asked now.” Keywords: brain developmentbrain plasticitycell biologycortical neurondevelopmental biologydevelopmental delaygrowthhuman cognitionmetabolismmicrobiologymitochondriamouse brainneural developmentneuronal plasticityneuronsNewsNews Brief

reposted from
http://www.eurekalert.org/pub_releases/2013-08/uoc--eop081613.php


Public release date: 16-Aug-2013
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Contact: Jeffrey Norris
jeff.norris@ucsf.edu
415-502-6397
University of California - San Francisco 

Effects of Parkinson's-disease mutation reversed in cells

UCSF study shows potential for new treatment strategy

UC San Francisco scientists working in the lab used a chemical found in an anti-wrinkle cream to prevent the death of nerve cells damaged by mutations that cause an inherited form of Parkinson’s disease. A similar approach might ward off cell death in the brains of people afflicted with Parkinson’s disease, the team suggested in a study reported online in the journal Cell on August 15.

The achievement marks a pharmacologic milestone as the first highly specific targeting of a member of an important class of enzymes called kinases to increase rather than to inhibit their activity, according to UCSF chemist Kevan Shokat, PhD, the senior scientist on the study. The research raises hope that similar pharmaceutical strategies might be used for combatting other diseases, including diabetes and cancer, he said.

Mutations that cause malfunction of the targeted enzyme, PINK1, are directly responsible for some cases of early-onset Parkinson’s disease. Loss of PINK1 activity is harmful to the cell’s power plants, called mitochondria, best known for converting food energy into another form of chemical energy used by cells, the molecule ATP.

In Parkinson’s disease, poorly performing mitochondria have been associated with the death of dopamine-producing nerve cells in a region of the brain called the substantia nigra, which plays a major role in control of movement. Loss of these cells is a hallmark of Parkinson’s disease and the cause of prominent symptoms including rigidity and tremor.

A UCSF team led by Shokat, a Howard Hughes Medical Institute Investigator, used the chemical, called kinetin, to increase mutant PINK1 enzyme activity in nerve cells to near normal levels.

“In light of the fact that mutations in PINK1 produce Parkinson’s disease in humans, the finding that kinetin can speed mutated PINK1 activity to near normal levels raises the possibility that kinetin may be used to treat these patients,” Shokat said.

The researchers also found that, in nerve cells with normal PINK1, kinetin boosted enzyme activity beyond typical levels. This finding may be relevant for the most common forms of Parkinson’s disease, in which PINK1 is not mutated, because a previous study showed that similar overactivity of PINK1 can slow the development of abnormal movement in a fruit-fly model of Parkinson’s disease caused by another defect. This defect is elevated production of the protein alpha-synuclein, also a cause of some inherited cases of Parkinson’s disease.

The demonstration in the new study that PINK1 can be boosted in human nerve cells that lack PINK1 mutations therefore suggests that kinetin might also have therapeutic potential in common cases of Parkinson’s disease in which PINK1 is not mutated, Shokat said.

Parkinson’s disease is the second most common neurodegenerative disease after Alzheimer’s disease, and the 14th leading cause of death in the United States, according to the U.S Centers for Disease Control and Prevention. Current treatments primarily aim to boost availability of dopamine to brain regions where dopamine-producing nerve cells have been lost.

Although many drugs that inhibit the activity of kinases have been developed over the past decade, including 15 currently approved to treat cancer, Shokat said none has yet been marketed to directly boost activity of a kinase.

The breakthrough in revving up PINK1 activity pharmacologically stemmed from Shokat’s unconventional approach. He targeted the enzyme’s “substrate,” a molecule that binds to an enzyme and undergoes a quick chemical transformation as a result. PINK1 uses ATP as a substrate, and the chemical reaction helps PINK1 in turn drive the activation of another enzyme, called Parkin.

Both of these enzymes are among a small number that previously have been strongly linked to Parkinson’s disease. PINK1 and Parkin act together to monitor the health of mitochondria, and help trigger repair or disposal of damaged mitochondria within the cells, thereby promoting cell survival.

“Therapeutic approaches for enhancing the activity of PINK1 had not been considered, because scientists had not conceived of the idea of developing a new substrate for the enzyme,” Shokat said.

“We found that a small molecule, called KTP, speeds chemical reactions catalyzed by PINK1 better than ATP, the natural substrate. That kind of better-than-natural response is essentially unheard of.”

KTP is too big to fit into other kinases, Shokat said, but PINK1 has a larger ATP “pocket” to hold KTP.

After discovering the potential of KTP, the researchers then determined that kinetin is converted to KTP within cells. Experimentally, kinetin, which can cross blood vessels to get into the brain, has been given by mouth to treat a rare, genetic, neurological disease called familial dysautonomia.

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Other researchers on the UCSF study include graduate student Nicholas Hertz, PhD; post-doctoral fellows Martin Sos, PhD and Amandine Berthet, PhD; UCSF faculty members Ken Nakamura, MD, PhD from the Gladstone Institute, and Kurt Thorn, PhD, and Al Burlingame, PhD.

The research was funded by the National Institutes for Health and by the Michael J. Fox Foundation.

Hertz and Shokat are inventors on a patent application related to kinetin and PINK1. UCSF has licensed the patent application to Mitokinin LLC, and Hertz and Shokat are cofounders and members of the company.

UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy, a graduate division with nationally renowned programs in basic biomedical, translational and population sciences, as well as a preeminent biomedical research enterprise and two top-ranked hospitals, UCSF Medical Center and UCSF Benioff Children’s Hospital.

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