已入深夜,您辛苦了!由于当前在线用户较少,发布求助请尽量完整地填写文献信息,科研通机器人24小时在线,伴您度过漫漫科研夜!祝你早点完成任务,早点休息,好梦!

Autophagy capacity and sub-mitochondrial heterogeneity shape Bnip3-induced mitophagy regulation of apoptosis

粒体自噬 细胞生物学 自噬 串扰 线粒体 生物 细胞凋亡 程序性细胞死亡 生物化学 物理 光学
作者
Sehyo Charley Choe,Anne Hamacher‐Brady,Nathan Brady
出处
期刊:Cell Communication and Signaling [BioMed Central]
卷期号:13 (1) 被引量:38
标识
DOI:10.1186/s12964-015-0115-9
摘要

Mitochondria are key regulators of apoptosis. In response to stress, BH3-only proteins activate pro-apoptotic Bcl2 family proteins Bax and Bak, which induce mitochondrial outer membrane permeabilization (MOMP). While the large-scale mitochondrial release of pro-apoptotic proteins activates caspase-dependent cell death, a limited release results in sub-lethal caspase activation which promotes tumorigenesis. Mitochondrial autophagy (mitophagy) targets dysfunctional mitochondria for degradation by lysosomes, and undergoes extensive crosstalk with apoptosis signaling, but its influence on apoptosis remains undetermined. The BH3-only protein Bnip3 integrates apoptosis and mitophagy signaling at different signaling domains. Bnip3 inhibits pro-survival Bcl2 members via its BH3 domain and activates mitophagy through its LC3 Interacting Region (LIR), which is responsible for binding to autophagosomes. Previously, we have shown that Bnip3-activated mitophagy prior to apoptosis induction can reduce mitochondrial activation of caspases, suggesting that a reduction to mitochondrial levels may be pro-survival. An outstanding question is whether organelle dynamics and/or recently discovered subcellular variations of protein levels responsible for both MOMP sensitivity and crosstalk between apoptosis and mitophagy can influence the cellular apoptosis decision event. To that end, here we undertook a systems biology analysis of mitophagy-apoptosis crosstalk at the level of cellular mitochondrial populations.Based on experimental findings, we developed a multi-scale, hybrid model with an individually adaptive mitochondrial population, whose actions are determined by protein levels, embedded in an agent-based model (ABM) for simulating subcellular dynamics and local feedback via reactive oxygen species signaling. Our model, supported by experimental evidence, identified an emergent regulatory structure within canonical apoptosis signaling. We show that the extent of mitophagy is determined by levels and spatial localization of autophagy capacity, and subcellular mitochondrial protein heterogeneities. Our model identifies mechanisms and conditions that alter the mitophagy decision within mitochondrial subpopulations to an extent sufficient to shape cellular outcome to apoptotic stimuli.Overall, our modeling approach provides means to suggest new experiments and implement findings at multiple scales in order to understand how network topologies and subcellular heterogeneities can influence signaling events at individual organelle level, and hence, determine the emergence of heterogeneity in cellular decisions due the actions of the collective intra-cellular population.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
PDF的下载单位、IP信息已删除 (2025-6-4)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
刚刚
1秒前
5秒前
英俊的铭应助尊敬代亦采纳,获得10
8秒前
8秒前
如意枫叶发布了新的文献求助10
8秒前
科研通AI2S应助有魅力乌采纳,获得10
9秒前
ZC完成签到,获得积分10
9秒前
百里飞扬完成签到,获得积分10
9秒前
漂亮白枫发布了新的文献求助10
10秒前
13秒前
13秒前
13秒前
14秒前
善学以致用应助漂亮白枫采纳,获得10
17秒前
Arui发布了新的文献求助10
18秒前
18秒前
19秒前
carl发布了新的文献求助10
21秒前
xxttt发布了新的文献求助10
22秒前
漫漫完成签到 ,获得积分10
23秒前
Hello应助故意的山河采纳,获得10
23秒前
23秒前
何茂郎完成签到,获得积分10
24秒前
24秒前
听风者完成签到 ,获得积分10
25秒前
syw完成签到,获得积分10
26秒前
赘婿应助carl采纳,获得10
26秒前
27秒前
27秒前
Akim应助hq_elife采纳,获得20
28秒前
www关闭了www文献求助
28秒前
29秒前
Sophia发布了新的文献求助10
29秒前
杨行肖发布了新的文献求助10
30秒前
31秒前
allshestar完成签到 ,获得积分0
31秒前
谨慎雪碧发布了新的文献求助30
35秒前
水蜜桃完成签到 ,获得积分10
35秒前
36秒前
高分求助中
A new approach to the extrapolation of accelerated life test data 1000
ACSM’s Guidelines for Exercise Testing and Prescription, 12th edition 500
‘Unruly’ Children: Historical Fieldnotes and Learning Morality in a Taiwan Village (New Departures in Anthropology) 400
Indomethacinのヒトにおける経皮吸収 400
Phylogenetic study of the order Polydesmida (Myriapoda: Diplopoda) 370
基于可调谐半导体激光吸收光谱技术泄漏气体检测系统的研究 350
Robot-supported joining of reinforcement textiles with one-sided sewing heads 320
热门求助领域 (近24小时)
化学 材料科学 医学 生物 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 遗传学 基因 物理化学 催化作用 冶金 细胞生物学 免疫学
热门帖子
关注 科研通微信公众号,转发送积分 3989857
求助须知:如何正确求助?哪些是违规求助? 3531994
关于积分的说明 11255679
捐赠科研通 3270758
什么是DOI,文献DOI怎么找? 1805053
邀请新用户注册赠送积分活动 882195
科研通“疑难数据库(出版商)”最低求助积分说明 809208