Mitophagy Controls Beige Adipocyte Maintenance Through a Parkin-dependent and UCP1-independent Mechanism

Overview

Journal Sci Signal

Specialties Cell Biology
Physiology
Science

Date 2018 Apr 26

PMID 29692364

Citations 79

Authors

Xiaodan Lu

Svetlana Altshuler-Keylin

Qiang Wang

Yong Chen

Carlos Henrique Sponton

Kenji Ikeda

Pema Maretich

Takeshi Yoneshiro

Shingo Kajimura

Affiliations

Soon will be listed here.

Abstract

Beige adipocytes are an inducible form of mitochondria-enriched thermogenic adipocytes that emerge in response to external stimuli, such as chronic cold exposure. We have previously shown that after the withdrawal of external stimuli, beige adipocytes directly acquire a white fat-like phenotype through autophagy-mediated mitochondrial degradation. We investigated the upstream pathway that mediates mitochondrial clearance and report that Parkin-mediated mitophagy plays a key role in the beige-to-white adipocyte transition. Mice genetically deficient in showed reduced mitochondrial degradation and retained thermogenic beige adipocytes even after the withdrawal of external stimuli. Norepinephrine signaling through the PKA pathway inhibited the recruitment of Parkin protein to mitochondria in beige adipocytes. However, mitochondrial proton uncoupling by uncoupling protein 1 (UCP1) was dispensable for Parkin recruitment and beige adipocyte maintenance. These results suggest a physiological mechanism by which external cues control mitochondrial homeostasis in thermogenic fat cells through mitophagy.

Citing Articles

Advances in Small-Molecule Fluorescent pH Probes for Monitoring Mitophagy.

Liu Y, Zhang D, Qu Y, Tang F, Wang H, Ding A Chem Biomed Imaging. 2024; 2(2):81-97.

PMID: 39474479 PMC: 11503929. DOI: 10.1021/cbmi.3c00070.

Mitophagy Responds to the Environmental Temperature and Regulates Mitochondrial Mass in Adipose Tissues.

Yamashita S, Kanki T Adv Exp Med Biol. 2024; 1461:229-243.

PMID: 39289285 DOI: 10.1007/978-981-97-4584-5_16.

Reversing Pdgfrβ signaling restores metabolically active beige adipocytes by alleviating ILC2 suppression in aged and obese mice.

Benvie A, Berry D Mol Metab. 2024; 89:102028.

PMID: 39278546 PMC: 11458544. DOI: 10.1016/j.molmet.2024.102028.

Reversing Pdgfrβ Signaling Restores Metabolically Active Beige Adipocytes by Alleviating ILC2 Suppression in Aged and Obese Mice.

Benvie A, Berry D bioRxiv. 2024; .

PMID: 38948810 PMC: 11212986. DOI: 10.1101/2024.06.17.599436.

The autophagic regulation of rosiglitazone-promoted adipocyte browning.

Li Y, Zheng W, Li X, Lue Z, Liu Y, Wu J Front Pharmacol. 2024; 15:1412520.

PMID: 38895627 PMC: 11184087. DOI: 10.3389/fphar.2024.1412520.

References

Evans T, Sergin I, Zhang X, Razani B . Target acquired: Selective autophagy in cardiometabolic disease. Sci Signal. 2017; 10(468). PMC: 5451512. DOI: 10.1126/scisignal.aag2298. View

Moscat J, Karin M, Diaz-Meco M . p62 in Cancer: Signaling Adaptor Beyond Autophagy. Cell. 2016; 167(3):606-609. PMC: 5114003. DOI: 10.1016/j.cell.2016.09.030. View

Palacino J, Sagi D, Goldberg M, Krauss S, Motz C, Wacker M . Mitochondrial dysfunction and oxidative damage in parkin-deficient mice. J Biol Chem. 2004; 279(18):18614-22. DOI: 10.1074/jbc.M401135200. View

Narendra D, Tanaka A, Suen D, Youle R . Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol. 2008; 183(5):795-803. PMC: 2592826. DOI: 10.1083/jcb.200809125. View

Harms M, Seale P . Brown and beige fat: development, function and therapeutic potential. Nat Med. 2013; 19(10):1252-63. DOI: 10.1038/nm.3361. View

Zhang Y, Goldman S, Baerga R, Zhao Y, Komatsu M, Jin S . Adipose-specific deletion of autophagy-related gene 7 (atg7) in mice reveals a role in adipogenesis. Proc Natl Acad Sci U S A. 2009; 106(47):19860-5. PMC: 2785257. DOI: 10.1073/pnas.0906048106. View

Shinoda K, Luijten I, Hasegawa Y, Hong H, Sonne S, Kim M . Genetic and functional characterization of clonally derived adult human brown adipocytes. Nat Med. 2015; 21(4):389-94. PMC: 4427356. DOI: 10.1038/nm.3819. View

Muller T, Lee S, Jastroch M, Kabra D, Stemmer K, Aichler M . p62 links β-adrenergic input to mitochondrial function and thermogenesis. J Clin Invest. 2012; 123(1):469-78. PMC: 3533288. DOI: 10.1172/JCI64209. View

Enerback S, Jacobsson A, Simpson E, Guerra C, Yamashita H, Harper M . Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese. Nature. 1997; 387(6628):90-4. DOI: 10.1038/387090a0. View

10.

Kelly D, Scarpulla R . Transcriptional regulatory circuits controlling mitochondrial biogenesis and function. Genes Dev. 2004; 18(4):357-68. DOI: 10.1101/gad.1177604. View

11.

Akabane S, Uno M, Tani N, Shimazaki S, Ebara N, Kato H . PKA Regulates PINK1 Stability and Parkin Recruitment to Damaged Mitochondria through Phosphorylation of MIC60. Mol Cell. 2016; 62(3):371-384. DOI: 10.1016/j.molcel.2016.03.037. View

12.

Martinez-Lopez N, Garcia-Macia M, Sahu S, Athonvarangkul D, Liebling E, Merlo P . Autophagy in the CNS and Periphery Coordinate Lipophagy and Lipolysis in the Brown Adipose Tissue and Liver. Cell Metab. 2015; 23(1):113-27. PMC: 4715637. DOI: 10.1016/j.cmet.2015.10.008. View

13.

Kirkin V, Lamark T, Sou Y, Bjorkoy G, Nunn J, Bruun J . A role for NBR1 in autophagosomal degradation of ubiquitinated substrates. Mol Cell. 2009; 33(4):505-16. DOI: 10.1016/j.molcel.2009.01.020. View

14.

Taylor D, Gottlieb R . Parkin-mediated mitophagy is downregulated in browning of white adipose tissue. Obesity (Silver Spring). 2017; 25(4):704-712. PMC: 5373982. DOI: 10.1002/oby.21786. View

15.

Yamamoto A, Friedlein A, Imai Y, Takahashi R, Kahle P, Haass C . Parkin phosphorylation and modulation of its E3 ubiquitin ligase activity. J Biol Chem. 2004; 280(5):3390-9. DOI: 10.1074/jbc.M407724200. View

16.

Matsuda N, Sato S, Shiba K, Okatsu K, Saisho K, Gautier C . PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy. J Cell Biol. 2010; 189(2):211-21. PMC: 2856912. DOI: 10.1083/jcb.200910140. View

17.

Ikeda K, Kang Q, Yoneshiro T, Camporez J, Maki H, Homma M . UCP1-independent signaling involving SERCA2b-mediated calcium cycling regulates beige fat thermogenesis and systemic glucose homeostasis. Nat Med. 2017; 23(12):1454-1465. PMC: 5727902. DOI: 10.1038/nm.4429. View

18.

Murakawa T, Yamaguchi O, Hashimoto A, Hikoso S, Takeda T, Oka T . Bcl-2-like protein 13 is a mammalian Atg32 homologue that mediates mitophagy and mitochondrial fragmentation. Nat Commun. 2015; 6:7527. PMC: 4501433. DOI: 10.1038/ncomms8527. View

19.

Aune U, Ruiz L, Kajimura S . Isolation and differentiation of stromal vascular cells to beige/brite cells. J Vis Exp. 2013; (73). PMC: 3641667. DOI: 10.3791/50191. View

20.

Kim K, Stevens M, Akter M, Rusk S, Huang R, Cohen A . Parkin is a lipid-responsive regulator of fat uptake in mice and mutant human cells. J Clin Invest. 2011; 121(9):3701-12. PMC: 3171101. DOI: 10.1172/JCI44736. View