Bcl-2-like protein 13 is a mammalian Atg32 homologue that mediates mitophagy and mitochondrial fragmentation

Murakawa, Tomokazu; Yamaguchi, Osamu; Hashimoto, Ayako; Hikoso, Shungo; Takeda, Toshihiro; Oka, Takahiro; Yasui, Hirofumi; Ueda, Hiroshi; Akazawa, Yasushi; Nakayama, Hiroyuki; Taneike, Manabu; Misaka, Tomofumi; Omiya, Shigemiki; Shah, Ajay M.; Yamamoto, Akira; Nishida, Keiya; Ohsumi, Yoshinori; Okamoto, Koji; Sakata, Yasushi; Otsu, Kinya

doi:10.1038/ncomms8527

Cited by 369 publications

(312 citation statements)

References 31 publications

(58 reference statements)

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“…However, a recent study reported that NBR1 is dispensable for PARK2-mediated mitophagy regardless of the presence or absence of p62 [27]. Thus, other mitophagy receptors, such as BCL2L13 and FKBP8, may be involved in the autophagic degradation of damaged mitochondria [28,29]. Further studies will hence be needed to determine the molecules that may compensate for p62 in p62 f/f :RIP-Cre mice.…”

Section: Discussionmentioning

confidence: 99%

Normal pancreatic β-cell function in mice with <i>RIP-Cre</i>-mediated inactivation of p62/SQSTM1

et al. 2018

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Abstract. Recent studies have suggested that decreased pancreatic β-cell function and mass are common features of patients with type 2 diabetes mellitus. Pancreatic β-cell homeostasis is regulated by various types of signaling molecules and stress responses. Sequestosome 1/p62 (SQSTM1, hereafter referred to as p62) is a ubiquitin-binding adaptor protein involved in cell signaling, oxidative stress, and autophagy. Because p62 appears to play an important role in maintaining mitochondrial quality control, it is possible that the loss of p62 in pancreatic β cells contributes to mitochondrial dysfunction, and thus leading to impaired glucose tolerance. In this study we investigated the physiological roles of p62 by inactivating p62 in a β-cell specific manner. We found that firstly, rat insulin-2 promoter-Cre (RIP-Cre)-mediated p62 inactivation did not cause body weight gain, although ubiquitous inactivation of p62 was previously shown to result in severe obesity. Secondly, we found no gross structural disorganization of the islets of p62-deficient mice. Consistent with normal islet morphology, no impairment in glucose tolerance was observed in mice with RIP-Cre-mediated p62 deletion. These results suggest that p62 is dispensable for normal islet organization and β-cell function.Key words: Islets, β cell, Diabetes, p62, Sequestosome 1 TYPE 2 DIABETES MELLITUS is a metabolic disorder characterized by hyperglycemia resulting from the complex interplay of multiple genetic and environmental factors, resulting in both decreased insulin action on target tissues and defective pancreatic β-cell insulin secretion in response to glucose [1]. The natural history of diabetes is strongly associated with the disability of pan-

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Section: Discussionmentioning

confidence: 99%

Normal pancreatic β-cell function in mice with <i>RIP-Cre</i>-mediated inactivation of p62/SQSTM1

et al. 2018

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“…82 Bcl2-L-13 is ubiquitously and highly expressed in heart, skeletal muscle and the pancreas, 87 and localized in the outer mitochondrial membrane. 82 The second WXXL/I motif at residues 273-276 was a functional LC3-interacting region. Bcl2-L-13 was essential for a mitochondrial uncoupler, carbonyl cyanide m-chlorophenyl hydrazone-induced mitochondrial fragmentation and mitophagy.…”

Section: Mitochondrial Degradation In Hfmentioning

confidence: 99%

Sterile Inflammation and Degradation Systems in Heart Failure

Nishida

Otsu

2017

Circ J

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In most patients with chronic heart failure (HF), levels of circulating cytokines are elevated and the elevated cytokine levels correlate with the severity of HF and prognosis. Various stresses induce subcellular component abnormalities, such as mitochondrial damage. Damaged mitochondria induce accumulation of reactive oxygen species and apoptogenic proteins, and subcellular inflammation. The vicious cycle of subcellular component abnormalities, inflammatory cell infiltration and neurohumoral activation induces cardiomyocyte injury and death, and cardiac fibrosis, resulting in cardiac dysfunction and HF. Quality control mechanisms at both the protein and organelle levels, such as elimination of apoptogenic proteins and damaged mitochondria, maintain cellular homeostasis. An imbalance between protein synthesis and degradation is likely to result in cellular dysfunction and disease. Three major protein degradation systems have been identified, namely the cysteine protease system, autophagy, and the ubiquitin proteasome system. Autophagy was initially believed to be a non-selective process. However, recent studies have described the process of selective mitochondrial autophagy, known as mitophagy. Elimination of damaged mitochondria by autophagy is important for maintenance of cellular homeostasis. DNA and RNA degradation systems also play a critical role in regulating inflammation and maintaining cellular homeostasis mediated by damaged DNA clearance and post-transcriptional regulation, respectively. This review discusses some recent advances in understanding the role of sterile inflammation and degradation systems in HF.

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“…However, no homologs or functional homologs of Atg11 have been identified in mammalian cells. In mammalian cells, BCL2L13/Bcl-rambo plays an important role in mitophagy, and act as a functional homolog of Atg32 [41]. Full details of the function of BCL2L13 will be described later.…”

Section: Accepted M Manuscriptmentioning

confidence: 99%