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Mitochondrial Homeostasis in Adipose Tissue Remodeling


Mitochondrial Homeostasis in Adipose Tissue Remodeling

Svetlana Altshuler-Keylin et al. Sci Signal.


Mitochondrial homeostasis is regulated by a balance between mitochondrial biogenesis and degradation. Emerging evidence suggests that mitophagy, a selective form of autophagy that degrades mitochondria, plays a key role in the physiology and pathophysiology of mitochondria-enriched cells, such as brown and beige adipocytes. This review discusses findings regarding the roles of autophagy and mitophagy in cellular development, maintenance, and functions of metabolic organs, including adipose tissue, liver, and pancreas. A better understanding of the molecular links between mitophagy and energy metabolism will help to identify promising targets for the treatment of obesity and obesity-associated disorders.


Fig. 1
Fig. 1. Regulation of mitochondrial dynamics
Mitochondrial content is regulated by abalancebetweenmitochondrialbiogenesisanddegradation. Nuclear-codedtranscriptional 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.
Fig. 2
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
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
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.

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