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Powering up: growing neurons make an energy jump

Our brains can survive only for a few minutes without oxygen. Research has now identified that a dramatic metabolic shift occurs in developing neurons, from glucose to oxygen as their primary source of energy.

The findings, published in the journal eLife, reveal a metabolic route we think can also go wrong in cancer and neurodegenerative diseases, such as Alzheimer's and Parkinson's.

"There is relatively little understanding about how neuron metabolism is first established. Aside from enabling us to understand the process of neuronal development, this work also allows us to better understand neurodegenerative disease."

Tony Hunter PhD, Professor, Molecular and Cell Biology Laboratory, holder of the Renato Dulbecco Chair, and co-senior author, Salk Institute for Biological Studies, La Jolla, United States.

To send messages along neurons is energetically demanding, and the brain uses both oxygen and glucose intensely. For example, the brain uses 20 percent of the body's glucose (sugar) supply. A cell also has energy-producing factories, called mitochondria, scattered throughout the long, slender axons of neurons. Mitochondria provide all parts of the neuron with a constant supply of energy. As neurons get bigger, so grows the number of mitochondria, according to the new study.

We make new neurons in the womb, a process which continues after birth. A few areas in the adult brain continue to make new neurons throughout life. "We assume that the metabolic shift we describe in this new study happens every time a progenitor cell turns into a neuron," says the study's first author Xinde Zheng, research associate in the Cell Biology Laboratory at Salk Institute.

Cells that become neurons initially use a pathway called glycolysis — a major energy-producing process in the cell — where cytoplasm turns glucose into energy or ATP (adenosine triphosphate).

However, cells later switch to a more efficient pathway called oxidative phosphorylation.

Now the cell uses oxygen to produce ATP and that process occurs inside mitochondria.

Hunter, Zheng, Salk's Leah Boyer and other colleagues had previously studied a rare metabolic disease called Leigh syndrome, recently publishing work showing that less ATP is produced in Leigh's afflicted neurons.

In the process of understanding Leigh disease, they needed to see mutations as they occur within mitochondrial DNA. But, they could not find in published research how normally dividing cells generate energy before dividing and differentiating into new cell types.

In this study, Hunter's team saw that as a pre-neuron cell is becomming a neuron, genes coding for glycolysis switch off at the same time as key regulators of oxidative phosphorylation start up.

It was surprising for them to find developing neurons completely shut down glycolysis. And, that if they prevented that shut down, neurons died.

"This is the first comprehensive analysis of metabolic changes during neuronal differentiation. The surprising reliance of neurons on oxidative phosphorylation for their sole energy source has clear implications for neuronal vulnerability with age," explains co-senior investigator Rusty Gage, a professor in Salk's Laboratory of Genetics and holder of the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Diseases.

The group now plans to intensely study how metabolic genes work in developing cells. They want to see how neurons with energy defects associated with disease compare to other, finer differences in metabolism.

How metabolism is reprogrammed during neuronal differentiation is unknown. We found that the loss of hexokinase (HK2) and lactate dehydrogenase (LDHA) expression, together with a switch in pyruvate kinase gene splicing from PKM2 to PKM1, marks the transition from aerobic glycolysis in neural progenitor cells (NPC) to neuronal oxidative phosphorylation. The protein levels of c-MYC and N-MYC, transcriptional activators of the HK2 and LDHA genes, decrease dramatically. Constitutive expression of HK2 and LDHA during differentiation leads to neuronal cell death, indicating that the shut-off aerobic glycolysis is essential for neuronal survival. The metabolic regulators PGC-1α and ERRγ increase significantly upon neuronal differentiation to sustain the transcription of metabolic and mitochondrial genes, whose levels are unchanged compared to NPCs, revealing distinct transcriptional regulation of metabolic genes in the proliferation and post-mitotic differentiation states. Mitochondrial mass increases proportionally with neuronal mass growth, indicating an unknown mechanism linking mitochondrial biogenesis to cell size.

Other authors on the study are Mingji Jin, Jerome Mertens, Yongsung Kim, Li Ma, Li Ma, and Michael Hamm, all of the Salk Institute.

The research was supported by the National Institutes of Health, the G. Harold and Leila Y. Mathers Charitable Foundation, the JPB Foundation, the Leona M. and Harry B. Helmsley Charitable Trust, Annette Merle-Smith, the California Institute for Regenerative Medicine, and the Helmsley Center for Genomic Medicine.

About the Salk Institute for Biological Studies: Every cure has a starting point. The Salk Institute embodies Jonas Salk's mission to dare to make dreams into reality. Its internationally renowned and award-winning scientists explore the very foundations of life, seeking new understandings in neuroscience, genetics, immunology and more. The Institute is an independent nonprofit organization and architectural landmark: small by choice, intimate by nature and fearless in the face of any challenge. Be it cancer or Alzheimer's, aging or diabetes, Salk is where cures begin. Learn more at: salk.edu.
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Jul 14, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   

Salk Institute research has identified a dramatic metabolic shift in developing neurons.
Neurons become dependent on oxygen for energy after a key metabolic pathway is turned off.
As shown on the right, few GREEN neurons survive. RED cells are non-neural cells called glia..
Image Credit: Salk Institute



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