University Grenoble Alpes, Inserm, Laboratory of Fundamental and Applied Bioenergetics (LBFA) and SFR Environmental and Systems Biology (BEeSy), Grenoble, France.
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada.
Lab Invest. 2018 Feb;98(2):228-232. doi: 10.1038/labinvest.2017.113. Epub 2017 Oct 16.
Mitophagy is an emerging paradigm for mitochondrial quality control and cell homeostasis. Dysregulation of mitophagy can lead to human pathologies such as neurodegenerative disorders and contributes to the aging process. Complex protein signaling cascades have been described that regulate mitophagy. We have identified a novel lipid signaling pathway that involves the phospholipid cardiolipin (CL). CL is synthesized and normally confined at the inner mitochondrial membrane. However, upon a mitophagic trigger, ie, collapse of the inner membrane potential, CL is rapidly externalized to the mitochondrial surface with the assistance of the hexameric nucleoside diphosphate kinase D (NME4, NDPK-D, or NM23-H4). In addition to its NDP kinase activity, NME4/NDPK-D shows intermembrane phospholipid transfer activity in vitro and in cellular systems, which relies on NME4/NDPK-D interaction with CL, CL-dependent crosslinking of inner and outer mitochondrial membranes by symmetrical, hexameric NME4/NDPK-D, and a putative NME4/NDPK-D-based CL-transfer pathway. CL exposed at the mitochondrial surface then serves as an 'eat me' signal for the mitophagic machinery; it is recognized by the LC3 receptor of autophagosomes, targeting the dysfunctional mitochondrion to lysosomal degradation. Similar NME4-supported CL externalization is likely also involved in apoptosis and inflammatory reactions.
自噬是一种新兴的线粒体质量控制和细胞内稳态的范例。自噬的失调可导致人类疾病，如神经退行性疾病，并导致衰老过程。已经描述了调节自噬的复杂蛋白质信号级联。我们已经确定了一种新的脂质信号通路，涉及磷脂心磷脂 (CL)。CL 是在内质网膜上合成并正常局限的。然而，在自噬触发后，即内膜电位崩溃时，CL 在六聚核苷酸二磷酸激酶 D (NME4、NDPK-D 或 NM23-H4) 的帮助下迅速外排在线粒体表面。除了其 NDP 激酶活性外，NME4/NDPK-D 在体外和细胞系统中还显示出跨膜磷脂转移活性，这依赖于 NME4/NDPK-D 与 CL 的相互作用、CL 依赖性的内外膜交联通过对称的六聚体 NME4/NDPK-D 和假定的基于 NME4/NDPK-D 的 CL 转移途径。暴露在线粒体表面的 CL 随后作为自噬机制的“吃我”信号；它被自噬体的 LC3 受体识别，将功能失调的线粒体靶向溶酶体降解。类似的 NME4 支持的 CL 外化也可能参与细胞凋亡和炎症反应。
