Retrograde mitochondrial signaling governs the identity and maturity of metabolic tissues
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.
Authors
- Aaron Renberg (ORCID: https://orcid.org/0000-0002-8782-9342)
- Tracy Stromer
- Benjamin Thompson (ORCID: https://orcid.org/0000-0003-2035-1337)
- Leena Haataja (ORCID: https://orcid.org/0000-0003-3701-4679)
- Anne Lietzke (ORCID: https://orcid.org/0000-0003-1334-1181)
- Irina X. Zhang (ORCID: https://orcid.org/0000-0003-0078-1225)
- Emily M. Walker (ORCID: https://orcid.org/0000-0001-8394-1567)
- Gemma L. Pearson (ORCID: https://orcid.org/0000-0003-4253-1830)
- Vaibhav Sidarala (ORCID: https://orcid.org/0000-0002-8010-3418)
- Scott A. Soleimanpour (ORCID: https://orcid.org/0000-0001-6777-4498)
- Stephen C.J. Parker (ORCID: https://orcid.org/0000-0001-8122-0117)
- Elena Levi-D’Ancona (ORCID: https://orcid.org/0000-0002-4728-1976)
- Jin Li (ORCID: https://orcid.org/0000-0002-5743-696X)
- Sarah A. Ware (ORCID: https://orcid.org/0000-0002-2387-1613)
- Leslie S. Satin (ORCID: https://orcid.org/0000-0003-1355-8647)
- Peter Arvan (ORCID: https://orcid.org/0000-0002-4007-8799)
- Brett A. Kaufman (ORCID: https://orcid.org/0000-0003-4767-4937)
- Lori Sussel (ORCID: https://orcid.org/0000-0003-4672-7304)
- Michael L. Stitzel (ORCID: https://orcid.org/0000-0001-5630-559X)
- Nathan Lawlor (ORCID: https://orcid.org/0000-0003-3263-6057)
- Deqiang Zhang (ORCID: https://orcid.org/0000-0002-8849-2366)
- Emma C. Reck (ORCID: https://orcid.org/0009-0003-0784-1312)
- Kawthar Mohamed
- Nathan Qi
- Vishal S. Parekh (ORCID: https://orcid.org/0000-0001-6349-4077)
- Dre L. Hubers
- Ava M. Stendahl
- Lei Yin (ORCID: https://orcid.org/0000-0001-9237-9350)
- Jie Zhu (ORCID: https://orcid.org/0000-0001-7814-8943)
- Mabelle B. Pasmooij
Institutions
- University of Pittsburgh (US)
- University of Michigan (US)
- VA Ann Arbor Healthcare System (US)
- Michigan Medicine (US)
- Jackson Laboratory (US)
- University of Colorado Anschutz Medical Campus (US)
- UConn Health (US)
Publication Details
- Journal
- Science
- Published
- 2025-02-06
- DOI
- https://doi.org/10.1126/science.adf2034
- Citations
- 48
- Primary Topic
- Mitochondrial Function and Pathology
- Type
- article
- Field-Weighted Citation Impact
- 37.88