Hexokinase regulates Mondo-mediated longevity via the PPP and organellar dynamics

Author:

Laboy Raymond12ORCID,Ndoci Marjana1,Vonolfen Maximilian12,Ballhysa Eugen12,Syed Shamsh Tabrez1,Droth Tim1,Schilling Klara12,Löhrke Anna1,Atanassov Ilian1,Antebi Adam12ORCID

Affiliation:

1. Department of Molecular Genetics of Ageing, Max Planck Institute for Biology of Ageing

2. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne

Abstract

The transcriptional complex Mondo/Max-like, MML-1/MXL-2, acts as a convergent transcriptional regulatory output of multiple longevity pathways in Caenorhabditis elegans . These transcription factors coordinate nutrient sensing with carbohydrate and lipid metabolism across the evolutionary spectrum. While most studies have focused on the downstream outputs, little is known about the upstream inputs that regulate these transcription factors in a live organism. Here, we found that knockdown of various glucose metabolic enzymes decreases MML-1 localization in the nucleus and identified two hexokinase isozymes, hxk-1 and hxk-2, as the most vigorous regulators of MML-1 function. Upon hexokinase knockdown, MML-1 redistributes to mitochondria and lipid droplets (LD) and concomitantly, transcriptional targets are downregulated and germline longevity is abolished. Further, we found that hxk-1 regulates MML-1 through mitochondrial β-oxidation, while hxk-2 regulates MML-1 by modulating the pentose phosphate pathway (PPP) and its coordinated association with lipid droplets. Similarly, inhibition of the PPP rescues mammalian MondoA nuclear translocation and transcriptional function upon starvation. These studies reveal how metabolic signals and organellar communication regulate a key convergent metabolic transcription factor to promote longevity.

Publisher

eLife Sciences Publications, Ltd

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