ReviewMetabolism

Target acquired: Selective autophagy in cardiometabolic disease

See allHide authors and affiliations

Science Signaling  28 Feb 2017:
Vol. 10, Issue 468, eaag2298
DOI: 10.1126/scisignal.aag2298

Figures

  • Fig. 1 Accumulation of dysfunctional organelles in cardiometabolic disease.

    Organelle accumulation and dysfunction are common features of cardiometabolic diseases in nearly every tissue and cell type, including hepatocytes, macrophages, myocytes, cardiomyocytes, pancreatic islet β cells, and adipocytes. Specific players include lipid accumulation, mitochondrial dysfunction, protein aggregation, inflammasome activation, and peroxisome dysfunction.

  • Fig. 2 Selective autophagy degrades dysfunctional or excess organelles.

    Bottom: In cardiometabolic disease states, dysfunctional and/or excess organelles produce adverse signals that mediate disease pathology. Mitochondria and peroxisomes produce ROS, and mitochondria additionally release mitochondrial DNA (mtDNA) and incompletely oxidized lipid intermediates. Activated inflammasomes produce massive amounts of IL-1β. Lipid droplets are a relatively safe storage site for neutral lipids; their saturation results in lipotoxicity, ectopic lipid deposition, and membrane disruption. Protein aggregates are both inherently cytotoxic (proteotoxicity) and can activate inflammasomes as an example of pathological intraorganelle cross-talk. Top: Selective autophagy is a primary mode of degradation for each of these types of organelles and serves to both maintain intrinsic organelle function and limit toxic by-products. Archetypal steps in selective autophagy include tagging of dysfunctional or excess cargo (for example, by ubiquitin), recognition by selective autophagy receptors (for example, p62), delivery to the autophagosome, and fusion with the lysosome for complete degradation.

  • Fig. 3 Models of key molecular events mediating pexophagy, aggrephagy, and inflammasomophagy.

    (A) Aggrephagy: CHIP and Parkin are the main E3 ubiquitin ligases that target protein aggregates and inclusions. NBR1, p62, and ALFY interact with the autophagosome to mediate aggrephagy. (B) Inflammasomophagy: Inflammasomes are targeted for autophagic destruction through at least two routes. A mechanism termed precision autophagy involves direct recognition of multiple inflammasome components by TRIM20 (also known as MEFV), which recruits key components of autophagy machinery such as Beclin, ULK1, and ATG8 (top). Alternatively, upon polyubiquitination of the ASC subunit by a yet-to-be-identified E3 ligase, the inflammasome is recognized by p62 for autophagy (bottom). (C) Pexophagy: Mammalian pexophagy primarily proceeds through Pex2-mediated ubiquitination of Pex5. NBR1 serves as the main selective autophagy receptor for peroxisomes that mediates interaction with the autophagosome.

  • Fig. 4 Model of key molecular events that mediate mitophagy.

    Mitophagy likely proceeds through several complementary mechanisms. (Left) In response to mitochondrial damage, PINK1 phosphorylates ubiquitin to directly enhance NDP52 and OPTN binding. NDP52 and OPTN recruit several components of the autophagy machinery including ULK1 to initiate mitophagy. (Bottom) PINK1 also activates the E3 ubiquitin ligase Parkin, which targets many mitochondrial proteins. The deubiquitinase USP30 opposes Parkin to spare less-damaged mitochondria. Selective autophagy receptors for mitophagy include NDP52, OPTN, and p62. (Right) BNIP3 family proteins in the mitochondrial outer membrane directly mediate mitophagy by binding to LC3. (Center) Polyubiquitin/p62 oligomers cluster damaged mitochondria to favor mitophagy.

  • Fig. 5 Molecular mediators of lipophagy.

    (Left) Autophagosome recruitment to lipid droplets and downstream autophagosome-lysosome interaction depend on the activity of the small GTPase Rab7. (Center) The neutral lipases ATGL and HSL contain LC3-binding domains that are required for recruitment to the lipid droplet, constituting a mechanism for cross-talk between lipophagy and neutral lipolysis. (Right) PLIN2 and PLIN3 (PLIN2/3) proteins coat the lipid droplet surface and block both lipophagy and neutral lipolysis. Chaperone-mediated autophagy (CMA) targets PLIN2/3 using Hsc70 as an adapter, resulting in their direct translocation into lysosomes for degradation. This allows the machineries of both neutral lipolysis and lipophagy to access the lipid droplet.

  • Fig. 6 Transcriptional feedback control of selective autophagy.

    Several parallel feedback loops couple sensing of organelle damage with transcriptional regulation of selective autophagy genes. Under basal conditions, Keap1 binds to and targets Nrf2 for proteasomal degradation. Protein aggregates and dysfunctional mitochondria accumulate p62, which binds to and sequesters Keap1 to free Nrf2 and activate its transcriptional activity. Nrf2 targets many selective autophagy genes to degrade p62-tagged cargo. Similarly, TFEB translocates to the nucleus in response to mitochondrial and lysosomal stresses to transcribe selective autophagy, mitochondrial, and lysosomal genes.

Tables

  • Table 1 Therapeutic means of enhancing selective autophagy in metabolic disease.
    TreatmentSelective autophagy-related targets
    identified thus far
    Impacts on cardiometabolic diseases
    Behavioral interventions
    ExerciseBag3 (221), p62 (221), Nrf2 (241), TFEB (242), BNIP3 (243), and BRCA1 (244)Broad protection
    Caloric restriction (or fasting)BNIP3 (245), FOXO (245), TFEB (194, 246), Rab7 (164), p62 (247), and TFE3 (187)Broad protection
    Genetic models
    TFEBp62(43, 185) and other autophagy-lysosomal genes (43, 185, 186)↓ NAFLD (194), ↓ obesity/diabetes (194), and ↓ atherosclerosis (43)
    TFE3p62(192) among many autophagy-lysosomal genes (187, 192)↓ NAFLD (225, 248) and ↓ diabetes (225, 226)
    Pharmacological strategies
    Trehalosep62 (249) and other means of autophagy modulation (145, 232, 249251)↓ NAFLD (68, 232), ↓ diabetes (41, 68, 234), and ↓ endothelial dysfunction (145, 233)
    SpermidineATM (252), PINK1 (252), and Parkin (252)↓ Atherosclerosis (239) and ↓ endothelial dysfunction (144, 238)

Stay Connected to Science Signaling

Navigate This Article