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. 2025 Apr 11;388(6743):eadf2034.
doi: 10.1126/science.adf2034. Epub 2025 Apr 11.

Retrograde mitochondrial signaling governs the identity and maturity of metabolic tissues

Emily M Walker #  1 , Gemma L Pearson #  1 , Nathan Lawlor  2   3 , Ava M Stendahl  1 , Anne Lietzke  1 , Vaibhav Sidarala  1 , Jie Zhu  1 , Tracy Stromer  1 , Emma C Reck  1 , Jin Li  1 , Elena Levi-D'Ancona  1 , Mabelle B Pasmooij  1 , Dre L Hubers  1 , Aaron Renberg  1 , Kawthar Mohamed  1 , Vishal S Parekh  4 , Irina X Zhang  4 , Benjamin Thompson  4 , Deqiang Zhang  5 , Sarah A Ware  6 , Leena Haataja  1 , Nathan Qi  5 , Stephen C J Parker  7 , Peter Arvan  1 , Lei Yin  5 , Brett A Kaufman  6 , Leslie S Satin  4 , Lori Sussel  8 , Michael L Stitzel  2   3 , Scott A Soleimanpour  1   5   9
Affiliations

Retrograde mitochondrial signaling governs the identity and maturity of metabolic tissues

Emily M Walker et al. Science. .

Abstract

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 β 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 β 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.

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Conflict of interest statement

Competing interests: S.A.S has received grant funding from Ono Pharmaceutical Co., Ltd. and is a consultant for Novo Nordisk. All other authors declare that they have no competing interests.

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