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

被引:49
作者
Cook, Katherine L. [1 ,2 ]
Soto-Pantoja, David R. [3 ]
Abu-Asab, Mones [4 ]
Clarke, Pamela A. G. [1 ,2 ]
Roberts, David D. [3 ]
Clarke, Robert [1 ,2 ]
机构
[1] Georgetown Univ, Med Ctr, Dept Oncol, Washington, DC 20057 USA
[2] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA
[3] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA
[4] NEI, Immunopathol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA
关键词
Breast cancer; Mitochondria; Autophagy; Mitophagy; Parkin; Antiestrogen resistance; Fulvestrant; Imatinib; Estrogen receptor-a; BREAST-CANCER CELLS; ANTIESTROGEN RESISTANCE; RESPONSIVENESS; BIOGENESIS; APOPTOSIS; VACUOLE;
D O I
10.1186/2045-3701-4-16
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
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.
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页数:9
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