Mitochondria directly donate their membrane to form autophagosomes during a novel mechanism of parkin-associated mitophagy

Cell & Bioscience

Robert Clarke²  David D Roberts³  Pamela AG Clarke²  Mones Abu-Asab¹  David R Soto-Pantoja³  Katherine L Cook² 

[1] Immunopathology Section, Laboratory of Immunology, National Eye Institute National Institutes of Health, Bethesda, MD 20892, USA;Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA;Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA

关键词: Estrogen receptor-α;    Imatinib;    Fulvestrant;    Antiestrogen resistance;    Parkin;    Mitophagy;    Autophagy;    Mitochondria;    Breast cancer;   

Others  :  790959
DOI  :  10.1186/2045-3701-4-16

 received in 2013-11-13, accepted in 2014-02-06,  发布年份 2014

【 摘 要 】

Background

Autophagy (macroautophagy), a cellular process of “self-eating”, segregates damaged/aged organelles into vesicles, fuses with lysosomes, and enables recycling of the digested materials. The precise origin(s) of the autophagosome membrane is unclear and remains a critical but unanswered question. Endoplasmic reticulum, mitochondria, Golgi complex, and the plasma membrane have been proposed as the source of autophagosomal membranes.

Findings

Using electron microscopy, immunogold labeling techniques, confocal microscopy, and flow cytometry we show that mitochondria can directly donate their membrane material to form autophagosomes. We expand upon earlier studies to show that mitochondria donate their membranes to form autophagosomes during basal and drug-induced autophagy. Moreover, electron microscopy and immunogold labeling studies show the first physical evidence of mitochondria forming continuous structures with LC3-labeled autophagosomes. The mitochondria forming these structures also stain positive for parkin, indicating that these mitochondrial-formed autophagosomes represent a novel mechanism of parkin-associated mitophagy.

Conclusions

With the on-going debate regarding autophagosomal membrane origin, this report demonstrates that mitochondria can donate membrane materials to form autophagosomes. These structures may also represent a novel form of mitophagy where the mitochondria contribute to the formation of autophagosomes. This novel form of parkin-associated mitophagy may be a more efficient bio-energetic process compared with de novo biosynthesis of a new membrane, particularly if the membrane is obtained, at least partly, from the organelle being targeted for later degradation in the mature autolysosome.

【 授权许可】

   
2014 Cook et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

Figure 7.

【 参考文献 】

• [1]He C, Klionsky DJ: Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 2009, 43:67-93.
• [2]Mari M, Tooze SA, Reggiori F: The puzzling origin of the autophagosomal membrane. F1000 biology reports 2011, 3:25.
• [3]Rubinsztein DC, Shpilka T, Elazar Z: Mechanisms of autophagosome biogenesis. Current biology: CB 2012, 22:R29-R34.
• [4]Dunn WA Jr: Studies on the mechanisms of autophagy: formation of the autophagic vacuole. J Cell Biol 1990, 110:1923-1933.
• [5]Dunn WA Jr: Studies on the mechanisms of autophagy: maturation of the autophagic vacuole. J Cell Biol 1990, 110:1935-1945.
• [6]Hayashi-Nishino M, Fujita N, Noda T, Yamaguchi A, Yoshimori T, Yamamoto A: A subdomain of the endoplasmic reticulum forms a cradle for autophagosome formation. Nat Cell Biol 2009, 11:1433-1437.
• [7]Luo S, Chen Q, Cebollero E, Xing D: Mitochondria: one of the origins for autophagosomal membranes? Mitochondrion 2009, 9:227-231.
• [8]Hailey DW, Rambold AS, Satpute-Krishnan P, Mitra K, Sougrat R, Kim PK, Lippincott-Schwartz J: Mitochondria supply membranes for autophagosome biogenesis during starvation. Cell 2010, 141:656-667.
• [9]McEwan DG, Dikic I: Not all autophagy membranes are created equal. Cell 2010, 141:564-566.
• [10]Jin SM, Youle RJ: PINK1- and Parkin-mediated mitophagy at a glance. J Cell Sci 2012, 125:795-799.
• [11]Soto-Pantoja DR, Miller TW, Pendrak ML, DeGraff WG, Sullivan C, Ridnour LA, Abu-Asab M, Wink DA, Tsokos M, Roberts DD: CD47 deficiency confers cell and tissue radioprotection by activation of autophagy. Autophagy 2012, 8:1628-1642.
• [12]Cook KL, Shajahan AN, Clarke R: Autophagy and endocrine resistance in breast cancer. Expert Rev Anticancer Ther 2011, 11:1283-1294.
• [13]Clarke R, Shajahan AN, Riggins RB, Cho Y, Crawford A, Xuan J, Wang Y, Zwart A, Nehra R, Liu MC: Gene network signaling in hormone responsiveness modifies apoptosis and autophagy in breast cancer cells. J Steroid Biochem Mol Biol 2009, 114:8-20.
• [14]Schoenlein PV, Periyasamy-Thandavan S, Samaddar JS, Jackson WH, Barrett JT: Autophagy facilitates the progression of ERalpha-positive breast cancer cells to antiestrogen resistance. Autophagy 2009, 5:400-403.
• [15]Cook KL, Shajahan AN, Warri A, Jin L, Hilakivi-Clarke LA, Clarke R: Glucose-regulated protein 78 controls cross-talk between apoptosis and autophagy to determine antiestrogen responsiveness. Cancer Res 2012, 72:3337-3349.
• [16]Samaddar JS, Gaddy VT, Duplantier J, Thandavan SP, Shah M, Smith MJ, Browning D, Rawson J, Smith SB, Barrett JT, Schoenlein PV: A role for macroautophagy in protection against 4-hydroxytamoxifen-induced cell death and the development of antiestrogen resistance. Mol Cancer Ther 2008, 7:2977-2987.
• [17]Brunner N, Boysen B, Jirus S, Skaar TC, Holst-Hansen C, Lippman J, Frandsen T, Spang-Thomsen M, Fuqua SA, Clarke R: MCF7/LCC9: an antiestrogen-resistant MCF-7 variant in which acquired resistance to the steroidal antiestrogen ICI 182,780 confers an early cross-resistance to the nonsteroidal antiestrogen tamoxifen. Cancer Res 1997, 57:3486-3493.
• [18]Ertmer A, Huber V, Gilch S, Yoshimori T, Erfle V, Duyster J, Elsasser HP, Schatzl HM: The anticancer drug imatinib induces cellular autophagy. Leukemia 2007, 21:936-942.
• [19]Cook KL, Clarke R: Heat shock 70 kDa protein 5/glucose-regulated protein 78 "AMP"ing up autophagy. Autophagy 2012, 8:1827-1829.
• [20]Tu YF, Kaipparettu BA, Ma Y, Wong LJ: Mitochondria of highly metastatic breast cancer cell line MDA-MB-231 exhibits increased autophagic properties. Biochim Biophys Acta 1807, 2011:1125-1132.
• [21]Vazquez-Martin A, Oliveras-Ferraros C, Menendez JA: Autophagy facilitates the development of breast cancer resistance to the anti-HER2 monoclonal antibody trastuzumab. PLoS One 2009, 4:e6251.
• [22]Thomas S, Thurn KT, Bicaku E, Marchion DC, Munster PN: Addition of a histone deacetylase inhibitor redirects tamoxifen-treated breast cancer cells into apoptosis, which is opposed by the induction of autophagy. Breast Cancer Res Treat 2011, 130:437-447.