The non-apoptotic action of Bcl-xL: regulating Ca2+ signaling and bioenergetics at the ER-mitochondrion interface

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• 作者：Abasha Williams ; Teruo Hayashi ; Daniel Wolozny…
• 刊名：Journal of Bioenergetics and Biomembranes
• 出版年：2016
• 出版时间：June 2016
• 年：2016
• 卷：48
• 期：3
• 页码：211-225
• 全文大小：3,011 KB
• 刊物类别：Chemistry and Materials Science
• 刊物主题：Chemistry
  Bioorganic Chemistry
  Biochemistry
  Animal Anatomy, Morphology and Histology
  Animal Biochemistry
  Organic Chemistry
  
• 出版者：Springer New York
• ISSN：1573-6881
• 卷排序：48

文摘

Bcl-2 family proteins are known to competitively regulate Ca2+; however, the specific inter-organelle signaling pathways and related cellular functions are not fully elucidated. In this study, a portion of Bcl-x_L was detected at the ER-mitochondrion interface or MAM (mitochondria-associated ER membrane) in association with type 3 inositol 1,4,5-trisphosphate receptors (IP₃R3); an association facilitated by the BH4 and transmembrane domains of Bcl-x_L. Moreover, increasing Bcl-x_L expression enhanced transient mitochondrial Ca2+ levels upon ER Ca2+ depletion induced by short-term, non-apoptotic incubation with thapsigargin (Tg), while concomitantly reducing cytosolic Ca2+ release. These mitochondrial changes appear to be IP₃R3-dependent and resulted in decreased NAD/NADH ratios and higher electron transport chain oxidase activity. Interestingly, extended Tg exposure stimulated ER stress, but not apoptosis, and further enhanced TCA cycling. Indeed, confocal analysis indicated that Bcl-x_L translocated to the MAM and increased its interaction with IP₃R3 following extended Tg treatment. Thus, the MAM is a critical cell-signaling junction whereby Bcl-x_L dynamically interacts with IP₃R3 to coordinate mitochondrial Ca2+ transfer and alters cellular metabolism in order to increase the cells’ bioenergetic capacity, particularly during periods of stress.KeywordsBcl-x_LBioenergeticsCalicum signalingMitochondriaERMAMIP₃R3