Retrograde mitochondrial signaling governs the identity and maturity of metabolic tissues

• 成果类型: Article
• 署名作者: Walker, Emily M.; Pearson, Gemma L.; Lawlor, Nathan; Stendahl, Ava M.; Lietzke, Anne; Sidarala, Vaibhav; Zhu, Jie; Stromer, Tracy; Reck, Emma C.; Li, Jin; Levi-D'Ancona, Elena; Pasmooij, Mabelle B.; Hubers, Dre L.; Renberg, Aaron; Mohamed, Kawthar; Parekh, Vishal S.; Zhang, Irina X.; Thompson, Benjamin; Zhang, Deqiang; Ware, Sarah A.; Haataja, Leena; Qi, Nathan; Parker, Stephen C. J.; Arvan, Peter; Yin, Lei; Kaufman, Brett A.; Satin, Leslie S.; Sussel, Lori; Stitzel, Michael L.; Soleimanpour, Scott A.
• 署名单位: University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; Jackson Laboratory; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; University of Michigan System; University of Michigan; University of Colorado System; University of Colorado Anschutz Medical Campus; US Department of Veterans Affairs; Veterans Health Administration (VHA); VA Ann Arbor Healthcare System
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-12797
• DOI: 10.1126/science.adf2034
• 发表日期: 2025-04-10
• 页码: 167-+
• 关键词: beta-cell dedifferentiation; diabetes susceptibility gene; insulin-secretion; transcription factors; stress-response; adipose-tissue; dysfunction; expression; clec16a; muscle

摘要

Mitochondrial damage is a hallmark of metabolic diseases, including diabetes, yet the consequences of compromised mitochondria in metabolic tissues are often unclear. In this work, we report that dysfunctional mitochondrial quality control engages a retrograde (mitonuclear) signaling program that impairs cellular identity and maturity in beta cells, hepatocytes, and brown adipocytes. Targeted deficiency throughout the mitochondrial quality control pathway, including genome integrity, dynamics, or turnover, impaired the oxidative phosphorylation machinery, activating the mitochondrial integrated stress response, eliciting chromatin remodeling, and promoting cellular immaturity rather than apoptosis to yield metabolic dysfunction. Pharmacologic blockade of the integrated stress response in vivo restored beta cell identity after the loss of mitochondrial quality control. Targeting mitochondrial retrograde signaling may therefore be promising in the treatment or prevention of metabolic disorders.