The nuclear envelope (NE) is a dynamic and selective barrier that organizes genome function and nucleocytoplasmic communication, and its structural deterioration is a hallmark of aging associated with diverse human diseases. 

Now, researchers from the Institute of Genetics and Developmental Biology of the Chinese Academy of Sciences (CAS) have uncovered a previously unrecognized mechanism by which mitochondrial redox signaling preserves NE structure and delays aging. 

Published in Nature Metabolism on February 3, the study identifies mitochondrial superoxide as a key developmental signal that maintains nuclear integrity by regulating lipid metabolism.

The NE is stabilized through the coordinated control of the nuclear lamina, cytoskeletal forces, and membrane composition. Most studies have focused on mitotic NE dynamics, leaving the mechanisms that preserve NE structure in non-dividing aging cells poorly understood. Mitochondria are central hubs of metabolic and signaling activity. Mild mitochondrial perturbations can promote cellular homeostasis and longevity through adaptive stress responses. However, whether mitochondrial redox signals directly regulate NE integrity during aging, and how this occurs, has remained unclear.

Using the nematode Caenorhabditis elegans as a model system, the researchers demonstrated that  reducing mitochondrial electron transport chain (ETC) activity in C. elegans significantly preserves NE integrity during aging. This protective effect depends on mitochondrial superoxide generated during development. Mechanistically, mitochondrial superoxide suppresses the activity of SBP-1, the nematode ortholog of mammalian SREBP, leading to reduced synthesis of unsaturated fatty acids. The resulting decrease in lipid peroxidation limits age-associated damage to the NE, thereby maintaining nuclear structure and function.

Importantly, direct interventions that inhibit lipid peroxidation were sufficient to preserve NE integrity, extend the lifespan of C. elegans, and alleviate age-associated cellular defects in human fibroblasts and in monkey cell models of Hutchinson–Gilford progeria syndrome. 

These results suggest that lipid peroxidation is a critical downstream effector that links mitochondrial redox signaling to nuclear aging.

The study also identifies mitochondrial superoxide as a protective developmental signal that programs long-term NE stability. By establishing precise control of lipid peroxidation as a conserved strategy to delay nuclear aging, the study highlights redox-lipid crosstalk as a promising therapeutic approach to promote healthy aging and combat age-related diseases.

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