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J. Biol. Chem., Vol. 281, Issue 37, 27643-27652, September 15, 2006

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The Mammalian Target of Rapamycin (mTOR) Pathway Regulates Mitochondrial Oxygen Consumption and Oxidative Capacity^*

Stefan M. Schieke, Darci Phillips, J. Philip McCoy, Jr.^¶, Angel M. Aponte^||, Rong-Fong Shen^||, Robert S. Balaban, and Toren Finkel¹

From the Cardiology Branch, Laboratory of Cardiac Energetics, ^¶Flow Cytometry Core Facility, and ^||Proteomics Core Facility, NHLBI, National Institutes of Health, Bethesda, Maryland 20892

Metabolic rate and the subsequent production of reactive oxygen species are thought to contribute to the rate of aging in a wide range of species. The target of rapamycin (TOR) is a well conserved serine/threonine kinase that regulates cell growth in response to nutrient status. Here we demonstrate that in mammalian cells the mammalian TOR (mTOR) pathway plays a significant role in determining both resting oxygen consumption and oxidative capacity. In particular, we demonstrate that the level of complex formation between mTOR and one of its known protein partners, raptor, correlated with overall mitochondrial activity. Disruption of this complex following treatment with the mTOR pharmacological inhibitor rapamycin lowered mitochondrial membrane potential, oxygen consumption, and ATP synthetic capacity. Subcellular fractionation revealed that mTOR as well as mTOR-raptor complexes can be purified in the mitochondrial fraction. Using two-dimensional difference gel electrophoresis, we further demonstrated that inhibiting mTOR with rapamycin resulted in a dramatic alteration in the mitochondrial phosphoproteome. RNA interference-mediated knockdown of TSC2, p70 S6 kinase (S6K1), raptor, or rictor demonstrates that mTOR regulates mitochondrial activity independently of its previously identified cellular targets. Finally we demonstrate that mTOR activity may play an important role in determining the relative balance between mitochondrial and non-mitochondrial sources of ATP generation. These results may provide insight into recent observations linking the TOR pathway to life span regulation of lower organisms.

Received for publication, April 12, 2006 , and in revised form, June 23, 2006.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: NHLBI, National Institutes of Health, Bldg. 10CRC/5-3330, 10 Center Dr., Bethesda, MD 20892-1622. Tel.: 301-402-4081; E-mail: finkelt{at}nih.gov.

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