Dataset Information

Endophilin B2 promotes inner mitochondrial membrane degradation by forming heterodimers with Endophilin B1 during mitophagy.

ABSTRACT: Mitochondrial sequestration by autophagosomes is a key step in mitophagy while the mechanisms mediating this process are not fully understood. It has been reported that Endophilin B1 (EB1) promotes mitochondrial sequestration by binding and shaping membrane. However, the role of EB1 homolog Endophilin B2 (EB2) in mitophagy remains unclear. Here we report that EB2 plays an indispensable role in mitochondria sequestration and inner mitochondrial membrane (IMM) protein degradation during mitophagy. Similar to EB1, EB2 aggregates into foci and then translocates to damaged mitochondria. Loss of either EB2 and/or EB1 significantly enervates the foci translocation to fragmented mitochondria and IMM degradation, and the EB1/EB2 heterodimer formed by EB1/EB2 interaction promotes the above process. We noticed that, it is the dimer domain of EB2 but not that of EB1 mediating the heterodimer formation, manifesting the importance of EB2 in mitophagy. Furthermore, we demonstrate that the EB foci formation is closely regulated by the PINK1-Parkin signaling pathway. From these results, we propose that EB1/EB2 heterodimers may serve as linkers between damaged mitochondria and phagophores during mitophagy.

SUBMITTER: Wang YH

PROVIDER: S-EPMC4845016 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Endophilin B2 promotes inner mitochondrial membrane degradation by forming heterodimers with Endophilin B1 during mitophagy.

Wang Yi-Han YH Wang Jiu-Qiang JQ Wang Qiaochu Q Wang Yun Y Guo Caixia C Chen Quan Q Chai Tuanyao T Tang Tie-Shan TS

Scientific reports 20160426

Mitochondrial sequestration by autophagosomes is a key step in mitophagy while the mechanisms mediating this process are not fully understood. It has been reported that Endophilin B1 (EB1) promotes mitochondrial sequestration by binding and shaping membrane. However, the role of EB1 homolog Endophilin B2 (EB2) in mitophagy remains unclear. Here we report that EB2 plays an indispensable role in mitochondria sequestration and inner mitochondrial membrane (IMM) protein degradation during mitophagy. ...[more]

PMID: 27112121

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Project description:Endophilin-B1, also known as Bax-interacting factor 1 (Bif-1, and encoded by SH3GLB1), is a multifunctional protein involved in apoptosis, autophagy and mitochondrial function. We recently described a unique neuroprotective role for neuron-specific alternatively spliced isoforms of endophilin-B1. To examine whether endophilin-B1-mediated neuroprotection could be a novel therapeutic target for Alzheimer's disease we used a double mutant amyloid precursor protein and presenilin 1 (APPswe/PSEN1dE9) mouse model of Alzheimer's disease and observed that expression of neuron-specific endophilin-B1 isoforms declined with disease progression. To determine if this reduction in endophilin-B1 has a functional role in Alzheimer's disease pathogenesis, we crossed endophilin-B1(-/-) mice with APPswe/PSEN1dE9 mice. Deletion of endophilin-B1 accelerated disease onset and progression in 6-month-old APPswe/PSEN1dE9/endophilin-B1(-/-) mice, which showed more plaques, astrogliosis, synaptic degeneration, cognitive impairment and mortality than APPswe/PSEN1dE9 mice. In mouse primary cortical neuron cultures, overexpression of neuron-specific endophilin-B1 isoforms protected against amyloid-β-induced apoptosis and mitochondrial dysfunction. Additionally, protein and mRNA levels of neuron-specific endophilin-B1 isoforms were also selectively decreased in the cerebral cortex and in the synaptic compartment of patients with Alzheimer's disease. Flow sorting of synaptosomes from patients with Alzheimer's disease demonstrated a negative correlation between amyloid-β and endophilin-B1 levels. The importance of endophilin-B1 in neuronal function was further underscored by the development of synaptic degeneration and cognitive and motor impairment in endophilin-B1(-/-) mice by 12 months. Our findings suggest that endophilin-B1 is a key mediator of a feed-forward mechanism of Alzheimer's disease pathogenesis where amyloid-β reduces neuron-specific endophilin-B1, which in turn enhances amyloid-β accumulation and neuronal vulnerability to stress.

Dataset Information

Endophilin B2 promotes inner mitochondrial membrane degradation by forming heterodimers with Endophilin B1 during mitophagy.

Publications

Endophilin B2 promotes inner mitochondrial membrane degradation by forming heterodimers with Endophilin B1 during mitophagy.

Similar Datasets

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