Article

Microtubule-associated protein 1 light chain 3 (LC3) interacts with Bnip3 protein to selectively remove endoplasmic reticulum and mitochondria via autophagy.

Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California 92093, USA.
Journal of Biological Chemistry (Impact Factor: 4.6). 04/2012; 287(23):19094-104. DOI: 10.1074/jbc.M111.322933
Source: PubMed

ABSTRACT Autophagy plays an important role in cellular quality control and is responsible for removing protein aggregates and dysfunctional organelles. Bnip3 is an atypical BH3-only protein that is known to cause mitochondrial dysfunction and cell death. Interestingly, Bnip3 can also protect against cell death by inducing mitochondrial autophagy. The mechanism for this process, however, remains poorly understood. Bnip3 contains a C-terminal transmembrane domain that is essential for homodimerization and proapoptotic function. In this study, we show that homodimerization of Bnip3 is also a requirement for induction of autophagy. Several Bnip3 mutants that do not interfere with its mitochondrial localization but disrupt homodimerization failed to induce autophagy in cells. In addition, we discovered that endogenous Bnip3 is localized to both mitochondria and the endoplasmic reticulum (ER). To investigate the effects of Bnip3 at mitochondria or the ER on autophagy, Bnip3 was targeted specifically to each organelle by substituting the Bnip3 transmembrane domain with that of Acta or cytochrome b(5). We found that Bnip3 enhanced autophagy in cells from both sites. We also discovered that Bnip3 induced removal of both ER (ERphagy) and mitochondria (mitophagy) via autophagy. The clearance of these organelles was mediated in part via binding of Bnip3 to LC3 on the autophagosome. Although ablation of the Bnip3-LC3 interaction by mutating the LC3 binding site did not impair the prodeath activity of Bnip3, it significantly reduced both mitophagy and ERphagy. Our data indicate that Bnip3 regulates the apoptotic balance as an autophagy receptor that induces removal of both mitochondria and ER.

0 Followers
 · 
231 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Autophagy is an evolutionarily conserved process by which long-lived proteins and organelles are sequestered by autophagosomes and subsequently degraded by lysosomes for recycling. Autophagy is important for maintaining cardiac homeostasis and is a survival mechanism that is upregulated during stress or starvation. Accumulating evidence suggests that dysregulated or reduced autophagy is associated with heart failure and aging. Thus, modulating autophagy represents an attractive future therapeutic target for treating cardiovascular disease. Activation of autophagy is generally considered to be cardioprotective, whereas excessive autophagy can lead to cell death and cardiac atrophy. It is important to understand how autophagy is regulated to identify ideal therapeutic targets for treating disease. Here, we discuss the key proteins in the core autophagy machinery and describe upstream regulators that respond to extracellular and intracellular signals to tightly coordinate autophagic activity. We review various genetic and pharmacological studies that demonstrate the important role of autophagy in the heart and consider the advantages and limitations of approaches that modulate autophagy. © 2015 American Heart Association, Inc.
    Circulation Research 01/2015; 116(3):489-503. DOI:10.1161/CIRCRESAHA.116.303791 · 11.09 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Mitophagy is a selective form of macro-autophagy in which mitochondria are selectively targeted for degradation in autophagolysosomes. Mitophagy can have the beneficial effect of eliminating old and/or damaged mitochondria, thus maintaining the integrity of the mitochondrial pool. However, mitophagy is not only limited to the turnover of dysfunctional mitochondria but also promotes reduction of overall mitochondrial mass in response to certain stresses, such as hypoxia and nutrient starvation. This prevents generation of reactive oxygen species and conserves valuable nutrients (such as oxygen) from being consumed inefficiently, thereby promoting cellular survival under conditions of energetic stress. The failure to properly modulate mitochondrial turnover in response to oncogenic stresses has been implicated both positively and negatively in tumorigenesis, while the potential of targeting mitophagy specifically as opposed to autophagy in general as a therapeutic strategy remains to be explored. The challenges and opportunities that come with our heightened understanding of the role of mitophagy in cancer are reviewed here.
    01/2015; 3:4. DOI:10.1186/s40170-015-0130-8
  • [Show abstract] [Hide abstract]
    ABSTRACT: Mitochondrial fitness is central to heart health. In many cell types, mitochondria are dynamic, interconnected filamentous networks. By comparison, mitochondria of healthy postmitotic adult cardiomyocytes are shortened, round, hypodynamic organelles. Mitochondrial networks are absent in cardiomyocytes; fission, fusion, and organelle mobility are not normally observed. Nevertheless, mitochondrial fission factor Drp1 and fusion factors Mfn1, Mfn2, and Opa1 are abundant and indispensable in adult hearts. Here, we review recent insights into roles for mitochondrial dynamics factors not strictly related to morphometric remodeling, advancing the argument that fission and fusion of cardiomyocyte mitochondria support surveillance, sequestration, and mitophagic removal of damaged organelles. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell Metabolism 02/2015; 21(2):195-205. DOI:10.1016/j.cmet.2014.12.019 · 16.75 Impact Factor