title: Rheb and mammalian target of rapamycin in mitochondrial homoeostasis.
abstract: Mitochondrial dysfunction has been associated with various diseases, such as cancer, myopathies, neurodegeneration and obesity. Mitochondrial homoeostasis is achieved by mechanisms that adapt the number of mitochondria to that required for energy production and for the supply of metabolic intermediates necessary to sustain cell growth. Simultaneously, mitochondrial quality control mechanisms are in place to remove malfunctioning mitochondria. In the cytoplasm, the protein complex mTORC1 couples growth-promoting signals with anabolic processes, in which mitochondria play an essential role. Here, we review the involvement of mTORC1 and Rheb in mitochondrial homoeostasis. The regulatory processes downstream of mTORC1 affect the glycolytic flux and the rate of mitophagy, and include regulation of the transcription factors HIF1α and YY1/PGC-1α. We also discuss how mitochondrial function feeds back on mTORC1 via reactive oxygen species signalling to adapt metabolic processes, and highlight how mTORC1 signalling is integrated with the unfolded protein response in mitochondria, which in Caenorhabditis elegans is mediated via transcription factors such as DVE-1/UBL-5 and ATFS-1.
authors.affiliation: Molecular Cancer Research, Centre for Biomedical Genetics and Cancer Genomics Centre, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands.
authors.forename: Marlous J
authors.initials: MJ
authors.lastname: Groenewoud
authors.forename: Fried J T
authors.initials: FJ
authors.lastname: Zwartkruis
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000502:physiology; D005786:Gene Expression Regulation; D006019:Glycolysis; D006706:Homeostasis; D006801:Humans; D008322:Mammals / Q000502:physiology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D008928:Mitochondria / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000502:physiology; D046912:Multiprotein Complexes / Q000502:physiology*; D009479:Neuropeptides / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D020123:Sirolimus / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D024101:Mitochondrial Proteins; D046912:Multiprotein Complexes; D009479:Neuropeptides; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: Rheb; mammalian target of rapamycin; metabolism; mitochondria; mitophagy