Retrograde mitochondrial signaling governs the identity and maturity of metabolic tissues.
Document Type
Article
Publication Date
2-6-2025
Publication Title
Science
Keywords
JGM
JAX Source
Science. Forthcoming 2025:eadf2034
First Page
2034
Last Page
2034
ISSN
1095-9203
PMID
39913641
DOI
https://doi.org/10.1126/science.adf2034
Abstract
Mitochondrial damage is a hallmark of metabolic diseases, including diabetes, yet the consequences of compromised mitochondria in metabolic tissues are often unclear. Here, 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. Indeed, pharmacologic blockade of the integrated stress response in vivo restored β-cell identity following loss of mitochondrial quality control. Targeting mitochondrial retrograde signaling may therefore be promising in the treatment or prevention of metabolic disorders.
Recommended Citation
Walker E,
Pearson G,
Lawlor N,
Stendahl A,
Lietzke A,
Sidarala V,
Zhu J,
Stromer T,
Reck E,
Li J,
Levi-D'Ancona E,
Pasmooij M,
Hubers D,
Renberg A,
Mohamed K,
Parekh V,
Zhang I,
Thompson B,
Zhang D,
Ware S,
Haataja L,
Qi N,
Parker S,
Arvan P,
Yin L,
Kaufman B,
Satin L,
Sussel L,
Stitzel ML,
Soleimanpour S.
Retrograde mitochondrial signaling governs the identity and maturity of metabolic tissues. Science. Forthcoming 2025:eadf2034