Tightly coupled brain activity and cerebral ATP metabolic rate

^†Department of Radiology, Center for Magnetic Resonance Research and
^‡Department of Biomedical Engineering, University of Minnesota Medical School, Minneapolis, MN 55455

Edited by Marcus E. Raichle, Washington University School of Medicine, St. Louis, MO, and approved March 18, 2008 (received for review November 13, 2007)

Abstract

A majority of ATP in the brain is formed in the mitochondria through oxidative phosphorylation of ADP with the F₁F₀-ATP (ATPase) enzyme. This ATP production rate plays central roles in brain bioenergetics, function and neurodegeneration. In vivo ³¹P magnetic resonance spectroscopy combined with magnetization transfer (MT) is the sole approach able to noninvasively determine this ATP metabolic rate via measuring the forward ATPase reaction flux (F _f,ATPase). However, previous studies indicate lack of quantitative agreement between F _f,ATPase and oxidative metabolic rate in heart and liver. In contrast, recent work has shown that F _f,ATPase might reflect oxidative phosphorylation rate in resting human brains. We have conducted an animal study, using rats under varied brain activity levels from light anesthesia to isoelectric state, to examine whether the in vivo ³¹P MT approach is suitable for measuring the oxidative phosphorylation rate and its change associated with varied brain activity. Our results conclude that the measured F _f,ATPase reflects the oxidative phosphorylation rate in resting rat brains, that this flux is tightly correlated to the change of energy demand under varied brain activity levels, and that a significant amount of ATP energy is required for “housekeeping” under the isoelectric state. These findings reveal distinguishable characteristics of ATP metabolism between the brain and heart, and they highlight the importance of in vivo ³¹P MT approach to potentially provide a unique and powerful neuroimaging modality for noninvasively studying the cerebral ATP metabolic network and its central role in bioenergetics associated with brain function, activation, and diseases.

Footnotes

^§To whom correspondence should be addressed. E-mail: wei{at}cmrr.umn.edu
Author contributions: F.D., X.-H.Z., K.U., and W.C. designed research; F.D., X.-H.Z., Y.Z., and W.C. performed research; M.F. and N.Z. contributed new reagents/analytic tools; F.D., X.-H.Z., Y.Z., N.Z., and W.C. analyzed data; and F.D., X.-H.Z., K.U., and W.C. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
↵ ¶ In a reaction A ⇆ B, unidirectional rates are given as the rate of A → B or B → A, whereas the net rate is defined as the difference between the two unidirectional rates. The terms rate and flux are used interchangeably.
This article contains supporting information online at www.pnas.org/cgi/content/full/0710766105/DCSupplemental.