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

By S. Schieke, D. Phillips, J. P. Mccoy, A. Aponte, Rong‐Fong Shen, R. Balaban, Toren Finkel, Cardiology Branch. Journal of Biological Chemistry, 2006

643 citations recorded by the source corpus.

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.

Subfields: Aging, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/9ed13e7e918452a647c8ff0e61b38601fa143fb9

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Citations in the corpus

Mitochondrial DNA: more than an evolutionary bystander (2014, background): “Mammalian TOR (mTOR) and mitochondrial oxidative capacity are tightly linked (Schieke et al. 2006), and mTOR inhibition reduced the association of PGC-1a with the transcription factor YY1, leading to lower expression of several genes encoding mitochondrial proteins (Cunningham et al.”
Metformin, Independent of AMPK, Inhibits mTORC1 In a Rag GTPase-Dependent Manner (2010, background): “C mitochondrial oxidative phosphorylation, as compared to glycolysis, is the most efficient mechanism to produce ATP, most cultured cells depend on both processes to generate energy (Schieke et al., 2006).”
Mechanisms underlying acute protection from cardiac ischemia-reperfusion injury. (2008, background): “Addition of rapamycin to Jurkat cells for 12 hours decreased oxygen consumption and reduced phosphorylation of several mitochondrial proteins such as the voltage dependent anion channel (VDAC) and several mitochondrial dehydrogenases (218). mTOR was also shown to localize with mitochondria (218).”
Mitochondrial complex III ROS regulate adipocyte differentiation (2011, positive): “One output of activated mTORC1 is to positively regulate mitochondrial oxygen consumption in mammalian cells (Schieke et al., 2006).”
Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012, background): “…1970; Tallal et al., 1970). mTORC1 has also been shown to have direct effects on promoting mitochondrial biogenesis, in part via a transcriptional complex that promotes the function of PGC-1a (Bentzinger et al., 2008; Cunningham et al., 2007; Ramanathan and Schreiber, 2009; Schieke et al., 2006).”
Mitochondrial dysfunction: mechanisms and advances in therapy (2024, background): “119 Metabolomics pro ﬁ ling showed that mTOR independently regulated mitochondrial metabolism in regulatory T cells.”
mTOR signaling at a glance (2009, background): “Inhibition of mTORC1 by rapamycin lowers mitochondrial membrane potential, oxygen consumption and cellular ATP levels, and profoundly alters the mitochondrial phosphoproteome ( Schieke et al., 2006 ).”
Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress (2010, background): “Interestingly, mSIN1 contains regions of homology to Ras-binding domains and a pleckstrin homology (PH)-like domain, suggesting that mSIN1 may have additional roles beyond providing structural support for mTORC2 (Schroder et al., 2007).”
mTORC1 controls mitochondrial activity and biogenesis through 4E-BP-dependent translational regulation. (2013, result): “Consistent with previous findings (Cunningham et al., 2007; Schieke et al., 2006), loss of TSC2 expression increased mitochondrial respiration, mitochondrial DNA content, and ATP levels (Figures 5D– 5F).”
Milk Protein Synthesis in the Lactating Mammary Gland: Insights from Transcriptomics Analyses (2012, background): “A third mechanism is through an increase of cellular energy production by enhancing expression of glucose transporter 1 and some of the AA transporters, and by improving mitochondrial ATP synthesis [154].”