The mTOR pathway regulates mitochondrial oxygen consumption and oxidative capacity

Schieke SM, Phillips D, McCoy JP Jr, Aponte AM, Shen RF, Balaban RS, Finkel T
Source: J Biol Chem
Publication Date: (2006)
Issue: 281(37): 27643-52
Research Area:
Cancer Research/Cell Biology
Cells used in publication:
Species: human
Tissue Origin: kidney
Species: human
Tissue Origin: blood
Nucleofectorâ„¢ I/II/2b
Metabolic rate and the subsequent production of reactive oxygen species is 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 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, correlates with overall mitochondrial activity. Disruption of this complex following treatment with the mTOR pharmacological inhibitor rapamycin, lowers mitochondrial membrane potential, oxygen consumption and ATP synthetic capacity. Subcellular fractionation reveals that mTOR as well as mTOR-raptor complexes can be purified in the mitochondrial fraction. Using 2-Dimensional Difference Gel Electrophoresis (DIGE), we further demonstrate that inhibiting mTOR with rapamycin results in a dramatic alteration in the mitochondrial phospho-proteome. RNAi 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.