Figures
Fig. 1 Regulation of mitochondrial dynamics. Mitochondrial content is regulated by a balance between mitochondrial biogenesis and degradation. Nuclear-coded transcriptional regulators, such as PGC-1α, Nrf1 and Nrf2 (Nrf1/2), and Tfam, control mitochondrial biogenesis, whereas autophagy removes damaged or unwanted mitochondria. Sirt1, sirtuin 1. Credit: A. Kitterman/Science Signaling
Fig. 2 Overview of the autophagy and mitophagy pathways. (A) Autophagy begins with the formation of the isolation membrane. Initiation of the isolation membrane requires the ULK1 complex, which is regulated by mTORC1. The isolation membrane then encloses cytosolic components and elongates to completely enclose and form the autophagosome. The elongation and closure of the autophagosome involve two ubiquitin-like conjugation systems: One forms the ATG5-ATG12-ATG16L complex, and the other one forms the PE-conjugated LC3 (LC3-PE). LC3-PE is required for autophagosome formation and serves as a marker of autophagy. Subsequently, the autophagosome fuses with the lysosome, and the enclosed components are degraded by the lysosomal enzymes. The MiT/TFE family of transcription factors regulates transcription of lysosomal autophagy genes. (B) Selective mitochondrial degradation, or mitophagy, relies on autophagy receptors that can interact with LC3-PE proteins (green). In adapter-mediated, ubiquitin-dependent mitophagy (top), PINK1 stabilization recruits Parkin and promotes ubiquitination of proteins in the outer mitochondrial membrane. Ubiquitin chains are recognized by adapter proteins that also contain the LIR and promote encapsulation of the mitochondria by the autophagosome. In adapter-independent, ubiquitin-independent mitophagy, specific mitochondrial proteins, several of which have been identified, directly interact with LC3.
Fig. 3 Beige adipocyte development. Activation of the β3-AR signaling by cold exposure or agonists induces differentiation of precursors into UCP1-positive beige adipocytes. Activation of autophagy after the withdrawal of the stimulus triggers loss of mitochondrial content and conversion from beige to white adipocytes.
Fig. 4 Cross-talk between the mTOR and β3-AR signaling pathways in beige adipocytes. (A) Under nutrient-rich conditions, mTORC1 is activated and phosphorylates ULK1 and ATG13 to repress the ULK1 complex and block autophagy. In response to starvation, mTORC1 is inhibited, inducing autophagy. (B and C) Activation of PKA in response to β3-AR stimulation induces transcription of brown/beige adipocyte program and promotes mTORC1 activity to inhibit autophagy partly through regulation of MiT/TFE family of transcription factors. (D) PKA activation suppresses the expression of genes encoding MiT/TFE transcription factors, and its lysosomal and autophagy targets. (E) mTORC1 alters lysosomal and autophagy gene expression through regulating the nuclear-cytoplasmic shuttling of TFEB (an MiT/TFE family member). Active mTORC1 phosphorylates TFEB and blocks its translocation to the nucleus, preventing transcription of lysosomal and autophagy targets.
Tables
- Table 1 Overview of adipose tissue phenotypes in animals that lack autophagy-related genes.
Molecule System Adipocyte phenotype References Atg5 Total knockout WAT development is impaired. (40) Atg5 MEFs in vitro MEFs from total knockout mice have defects in white adipocyte differentiation in culture. (40) Atg5 Ucp1-Cre Beige adipocytes are maintained in the absence of browning stimuli and retain mitochondria and UCP1. (39) Atg7 aP2-Cre WAT is reduced and adipocytes have increased mitochondrial content with small lipid droplets. WAT in knockout mice contains increased numbers of beige adipocytes. Mice are protected from diet-induced obesity and insulin resistance. (42, 43) Atg7 Myf5-Cre Deletion in Myf5+ progenitors impairs BAT development and promotes beige fat development. (41) Atg7 Mlclf-Cre Deletion in skeletal muscle induces browning of WAT. (47) Atg7 Pomc-Cre Deletion in POMC neurons induces browning of WAT. (71) Atg12 Ucp1-Cre Beige adipocytes are maintained in the absence of browning stimuli and retain mitochondria and UCP1. Mice are protected from diet-induced obesity and insulin resistance. (39) p62 Total knockout Enlarged adipocytes due to lipid accumulation. Mice are obese, glucose intolerant, and have decreased insulin sensitivity. (106) p62 aP2-Cre Brown adipocytes accumulate defective mitochondria and have more lipid droplets. Mice are obese, glucose intolerant, and have decreased insulin sensitivity. (44) Parkin Total knockout Mice are resistant to high-fat diet–induced obesity. EpiWAT and BAT of these mice accumulate less lipid in response to a high-fat diet. (107) Raptor Adiponectin-Cre Browning of WAT is disrupted in response to chronic cold exposure. (56)
