Universität zu Köln

Ross, Jaime M., Oberg, Johanna, Brene, Stefan, Coppotelli, Giuseppe, Terzioglu, Mugen, Pernold, Karin, Goiny, Michel, Sitnikov, Rouslan ORCID: 0000-0002-0773-7983, Kehr, Jan ORCID: 0000-0002-2410-124X, Trifunovic, Aleksandra, Larsson, Nils-Goran ORCID: 0000-0001-5100-996X, Hoffer, Barry J. and Olson, Lars (2010). High brain lactate is a hallmark of aging and caused by a shift in the lactate dehydrogenase A/B ratio. Proc. Natl. Acad. Sci. U. S. A., 107 (46). S. 20087 - 20093. WASHINGTON: NATL ACAD SCIENCES. ISSN 0027-8424

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Abstract

At present, there are few means to track symptomatic stages of CNS aging. Thus, although metabolic changes are implicated in mtDNA mutation-driven aging, the manifestations remain unclear. Here, we used normally aging and prematurely aging mtDNA mutator mice to establish a molecular link between mitochondrial dysfunction and abnormal metabolism in the aging process. Using proton magnetic resonance spectroscopy and HPLC, we found that brain lactate levels were increased twofold in both normally and prematurely aging mice during aging. To correlate the striking increase in lactate with tissue pathology, we investigated the respiratory chain enzymes and detected mitochondrial failure in key brain areas from both normally and prematurely aging mice. We used in situ hybridization to show that increased brain lactate levels were caused by a shift in transcriptional activities of the lactate dehydrogenases to promote pyruvate to lactate conversion. Separation of the five tetrameric lactate dehydrogenase (LDH) isoenzymes revealed an increase of those dominated by the Ldh-A product and a decrease of those rich in the Ldh-B product, which, in turn, increases pyruvate to lactate conversion. Spectrophotometric assays measuring LDH activity from the pyruvate and lactate sides of the reaction showed a higher pyruvate. lactate activity in the brain. We argue for the use of lactate proton magnetic resonance spectroscopy as a noninvasive strategy for monitoring this hallmark of the aging process. The mtDNA mutator mouse allows us to conclude that the increased LDH-A/LDH-B ratio causes high brain lactate levels, which, in turn, are predictive of aging phenotypes.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Ross, Jaime M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Oberg, Johanna UNSPECIFIED UNSPECIFIED UNSPECIFIED Brene, Stefan UNSPECIFIED UNSPECIFIED UNSPECIFIED Coppotelli, Giuseppe UNSPECIFIED UNSPECIFIED UNSPECIFIED Terzioglu, Mugen UNSPECIFIED UNSPECIFIED UNSPECIFIED Pernold, Karin UNSPECIFIED UNSPECIFIED UNSPECIFIED Goiny, Michel UNSPECIFIED UNSPECIFIED UNSPECIFIED Sitnikov, Rouslan UNSPECIFIED orcid.org/0000-0002-0773-7983 UNSPECIFIED Kehr, Jan UNSPECIFIED orcid.org/0000-0002-2410-124X UNSPECIFIED Trifunovic, Aleksandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Larsson, Nils-Goran UNSPECIFIED orcid.org/0000-0001-5100-996X UNSPECIFIED Hoffer, Barry J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Olson, Lars UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-492444
DOI:	10.1073/pnas.1008189107
Journal or Publication Title:	Proc. Natl. Acad. Sci. U. S. A.
Volume:	107
Number:	46
Page Range:	S. 20087 - 20093
Date:	2010
Publisher:	NATL ACAD SCIENCES
Place of Publication:	WASHINGTON
ISSN:	0027-8424
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MITOCHONDRIAL-DNA DELETIONS; CEREBROSPINAL-FLUID LACTATE; OXIDATIVE-PHOSPHORYLATION; POINT MUTATIONS; SKELETAL-MUSCLE; MUTATOR MICE; MOUSE; GLUCOSE; PROTEIN; AGE Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/49244