fmo-4promotes longevity and stress resistance via ER to mitochondria calcium regulation inC. elegans

Author:

Tuckowski AM,Beydoun S,Kitto ES,Bhat AORCID,Howington MB,Sridhar A,Bhandari M,Chambers K,Leiser SF

Abstract

AbstractFlavin-containing monooxygenases (FMOs) are a conserved family of xenobiotic enzymes upregulated in multiple longevity interventions, including nematode and mouse models.Previous work supports thatC. elegans fmo-2promotes longevity, stress resistance, and healthspan by rewiring endogenous metabolism. However, there are fiveC. elegansFMOs and five mammalian FMOs, and it is not known whether promoting longevity and health benefits is a conserved role of this gene family. Here, we report that expression ofC. elegans fmo-4promotes lifespan extension and paraquat stress resistance downstream of both dietary restriction and inhibition of mTOR. We find that overexpression offmo-4in just the hypodermis is sufficient for these benefits, and that this expression significantly modifies the transcriptome. By analyzing changes in gene expression, we find that genes related to calcium signaling are significantly altered downstream offmo-4expression. Highlighting the importance of calcium homeostasis in this pathway,fmo-4overexpressing animals are sensitive to thapsigargin, an ER stressor that inhibits calcium flux from the cytosol to the ER lumen. This calcium/fmo-4interaction is solidified by data showing that modulating intracellular calcium with either small molecules or genetics can change expression offmo-4and/or interact withfmo-4to affect lifespan and stress resistance. Further analysis supports a pathway wherefmo-4modulates calcium homeostasis downstream of activating transcription factor-6 (atf-6), whose knockdown induces and requiresfmo-4expression. Together, our data identifyfmo-4as a longevity- promoting gene whose actions interact with known longevity pathways and calcium homeostasis.

Publisher

Cold Spring Harbor Laboratory

Cited by 1 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3