The co-evolution of mitochondria and the nucleus established constant mito-nuclear communication that is essential for both cellular and organismal homeostasis. As a cellular signaling hub, the mitochondria initiate retrograde signaling to relay their functional state to the nucleus when facing stress or perturbations, thereby triggering transcriptional programs to reestablish cellular homeostasis.

Recent studies have revealed that this communication extends beyond cellular boundaries to coordinate systemic adaptation, stress resilience, and the aging process across tissues.

In a review published in Molecular cell on February 5, Dr. TIAN Ye's group from the Institute of Genetics and Developmental Biology of the Chinese Academy of Sciences summarized mitochondrial stress responses from the organelle level to the systemic organismal network, providing deep insights into the core role of mito-nuclear communication in regulating physiology and aging.

The researchers outlined cell-autonomous mitochondrial stress response pathways, with a focus on the mechanisms of the mitochondrial unfolded protein response (UPR^mt) and the mitochondrial integrated stress response (ISR^mt). They detailed the mechanistic differences of UPR^mt between C. elegans and mammals and conducted an in-depth analysis of the OMA1-DELE1-HRI axis, which links mitochondrial dysfunction to the cytosolic ISR network and acts as a critical regulatory node controlling cell fate decisions and metabolic reprogramming under different stress conditions.

Furthermore, the review proposes a framework for systemic mito-nuclear communication organized around four dimensions: sensing, broadcasting, modulation, and response. The researchers summarized how local mitochondrial stress signals are converted into secreted mitokines, which are transmitted to distal tissues via neural circuits and the endocrine system.

The review discusses how the nervous and reproductive systems integrate these signals to balance the trade-offs between growth, reproduction, and longevity. It further emphasizes the significance of this systemic communication in coordinating metabolic flexibility, innate immunity, and transgenerational inheritance.

Looking ahead, the researchers suggested that precise intervention in this mito-nuclear communication could serve as potential therapeutic strategy for treating metabolic diseases and delaying aging.

This work was supported by the National Key Research and Development Program of China, the National Natural Science Foundation of China, the CAS Project for Young Scientists in Basic Research, etc.