Featured Research

from universities, journals, and other organizations

Circadian clock is key to firing up cell's furnace

Date:
September 19, 2013
Source:
Northwestern University
Summary:
Each of our cells has an energy furnace, and it is called a mitochondrion. A research team now has identified a new mode of timekeeping that involves priming the cell's furnace to properly use stored fuel when we are not eating. The interdisciplinary team has identified the "match" and "flint" responsible for lighting this tiny furnace. And the match is only available when the circadian clock says so, underscoring the importance of the biological timing system to metabolism.

Each of our cells has an energy furnace, and it is called a mitochondrion. A Northwestern University-led research team now has identified a new mode of timekeeping that involves priming the cell's furnace to properly use stored fuel when we are not eating.

The interdisciplinary team has identified the "match" and "flint" responsible for lighting this tiny furnace. And the match is only available when the circadian clock says so, underscoring the importance of the biological timing system to metabolism.

"Circadian clocks are with us on Earth because they have everything to do with energy," said Joe Bass, M.D., who led the research. "If an organism burns its energy efficiently, it has a better chance of survival. Our results tell us how the circadian clock triggers the cell's energy-burning process. Cells are most capable of using fuel when the clock is working properly."

Bass is the Charles F. Kettering Professor and chief of the division of endocrinology, metabolism and molecular medicine at Northwestern University Feinberg School of Medicine and an endocrinologist at Northwestern Memorial Hospital.

Mitochondria regulate the supply of energy to cells when we are at rest, with no glucose available from food. In a study of mice, the researchers found that the circadian clock supplies the match to light the furnace and on the match tip is a critical compound called NAD+. It combines with an enzyme in mitochondria called Sirtuin 3, which acts as the flint, to light the furnace. When the clock in an animal isn't working, the animal can't metabolize stored energy and the process doesn't ignite.

This pathway through which the body clock controls activities within the mitochondria shows how energy generation is tied tightly to the light-dark/activity-rest cycle each day.

The findings, which could be useful in the development of therapies to treat metabolic disorders related to circadian disruption, will be published by the journal Science.

The results demonstrate that the circadian clock, a genetic timekeeper that evolved to enable organisms to track the daily transition from light to darkness early in evolution, generates oscillations in mitochondrial energy capacity through rhythmic regulation of NAD+ biosynthesis.

The clock facilitates oxidative rhythms that anticipate an animal's fasting/feeding cycle that occurs during the transition from light to darkness and wakefulness to sleep each day, and, in so doing, prevents the cell from "starving" during the night.

To understand how mitochondria are affected by circadian clock disorder, the researchers genetically removed the clocks in laboratory mice and compared them to controls. Both groups of mice were studied in a state of fasting; this "stress" test enabled the researchers to pinpoint just how the clock maintains "energy reserves" (akin to stress testing of a bank).

Bass and his research group worked together with Navdeep S. Chandel, a colleague of Bass' at Feinberg, and John M. Denu, at the University of Wisconsin-Madison. They found the mice lacking clocks had defects in their mitochondria: the mitochondria could not metabolize stored energy and had no reserve to prevent depletion of the main currency, ATP. (Adenosine triphosphate is an energy-bearing molecule found in all living cells.)

Working with Northwestern colleague Milan Mrksich, they went on to show that removal of the clock depletes the necessary ingredient to turn on an enzyme within mitochondria, Sirtuin 3, which activates energy burning during fasting.

The researchers also showed that when the circadian clock was disrupted, resulting in a lack of NAD+, they could provide NAD+ supplements and restore function to the mitochondrion.

The findings expand the understanding of the molecular pathways linking the circadian clock with metabolism and show that the clock provides an essential buffer to stabilize the cell as organisms transition between eating and fasting each day. This knowledge has implications for disease intervention and prevention, including of diabetes, and potentially for states of increased cell demand for metabolism (including inflammation and cancer).

"We have established the chain of events that couples the clock's control switch with the machinery of the mitochondria," said Bass, who also is a member of the department of neurobiology at the Weinberg College of Arts and Sciences. "We now have identified an additional link in the supply chain that provides energy to the cell at different phases of our daily sleep-wake cycle. These findings establish a key role for the NAD+ biosynthetic cycle in this process."

Major senior authors from Northwestern include Chandel, a professor in medicine-pulmonary and cell and molecular biology at Feinberg, and Mrksich, the Henry Wade Rogers Professor of Biomedical Engineering, Chemistry and Cell and Molecular Biology at Feinberg, Weinberg and the McCormick School of Engineering and Applied Science. Chandel and Mrksich are members of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

The co-first authors are Clara Bien Peek, a postdoctoral fellow, and Alison H. Affinati, an M.D./Ph.D. candidate, both working in Bass' lab. They have literally worked around the clock on the research, which builds on the earlier work of co-author Kathryn Moynihan Ramsey. In 2009, she and colleagues reported in Science that the compound NAD, together with the enzyme SIRT1, functions as a molecular "switch" to coordinate the internal clock with metabolic systems.

The current research team combined Northwestern expertise in basic circadian clock research, chemistry and physiology with outside collaborators who were able to verify the Northwestern findings.

Co-author Eric Goetzman, from the University of Pittsburgh School of Medicine, an expert in the rare children's disease called metabolic myopathy, was able to confirm that the pattern the researchers observed in mice was the same as that seen in these children. Fasting can be life-threatening for children with this disorder because they can't metabolize stored energy due to defects in their mitochondria.


Story Source:

The above story is based on materials provided by Northwestern University. Note: Materials may be edited for content and length.


Journal Reference:

  1. Clara Bien Peek, Alison H. Affinati, Kathryn Moynihan Ramsey, Hsin-Yu Kuo, Wei Yu, Laura A. Sena, Olga Ilkayeva, Biliana Marcheva, Yumiko Kobayashi, Chiaki Omura, Daniel C. Levine, David J. Bacsik, David Gius, Christopher B. Newgard, Eric Goetzman, Navdeep S. Chandel, John M. Denu, Milan Mrksich, and Joseph Bass. Circadian Clock NAD Cycle Drives Mitochondrial Oxidative Metabolism in Mice. Science, September 2013 DOI: 10.1126/science.1243417

Cite This Page:

Northwestern University. "Circadian clock is key to firing up cell's furnace." ScienceDaily. ScienceDaily, 19 September 2013. <www.sciencedaily.com/releases/2013/09/130919142158.htm>.
Northwestern University. (2013, September 19). Circadian clock is key to firing up cell's furnace. ScienceDaily. Retrieved July 22, 2014 from www.sciencedaily.com/releases/2013/09/130919142158.htm
Northwestern University. "Circadian clock is key to firing up cell's furnace." ScienceDaily. www.sciencedaily.com/releases/2013/09/130919142158.htm (accessed July 22, 2014).

Share This




More Health & Medicine News

Tuesday, July 22, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Gilead's $1000-a-Pill Drug Could Cure Hep C in HIV-Positive People

Gilead's $1000-a-Pill Drug Could Cure Hep C in HIV-Positive People

TheStreet (July 21, 2014) New research shows Gilead Science's drug Sovaldi helps in curing hepatitis C in those who suffer from HIV. In a medical study, the combination of Gilead's Hep C drug with anti-viral drug Ribavirin cured 76% of HIV-positive patients suffering from the most common hepatitis C strain. Hepatitis C and related complications have been a top cause of death in HIV-positive patients. Typical medication used to treat the disease, including interferon proteins, tended to react badly with HIV drugs. However, Sovaldi's %1,000-a-pill price tag could limit the number of patients able to access the treatment. TheStreet's Keris Lahiff reports from New York. Video provided by TheStreet
Powered by NewsLook.com
$23.6 Billion Awarded To Widow In Smoking Lawsuit

$23.6 Billion Awarded To Widow In Smoking Lawsuit

Newsy (July 20, 2014) Cynthia Robinson claims R.J. Reynolds Tobacco Company hid the health and addiction risks of its products, leading to the death of her husband in 1996. Video provided by Newsy
Powered by NewsLook.com
Tooth Plaque Provides Insight Into Diets Of Ancient People

Tooth Plaque Provides Insight Into Diets Of Ancient People

Newsy (July 19, 2014) Research on plaque from ancient teeth shows that our prehistoric ancestor's had a detailed understanding of plants long before developing agriculture. Video provided by Newsy
Powered by NewsLook.com
Contaminated Water Kills 3 Babies in South African Town

Contaminated Water Kills 3 Babies in South African Town

AFP (July 18, 2014) Contaminated water in South Africa's northwestern town of Bloemhof kills three babies and hospitalises over 500 people. The incident highlights growing fears over water safety in South Africa. Duration: 02:22 Video provided by AFP
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins