In localized scleroderma, contact sites between mitochondria and the endoplasmic reticulum proliferate and shuttle excess calcium, driving fibroblast senescence and fibrosis. Parthenolide, a sesquiterpene lactone, suppressed the oxidoreductase Ero1L at residue ARG-449, restored normal calcium handling through the IP3R1/Grp75/VDAC1 complex, and reduced both senescence and collagen deposition in cultured human dermal fibroblasts and a bleomycin-induced murine model. A thermosensitive sustained-release hydrogel formulation delivered comparable therapeutic effect locally.
Key Points
- Excess mitochondria-ER contact sites drive calcium overload in scleroderma skin
- Parthenolide suppresses Ero1L, restoring calcium transport and reversing fibroblast senescence
- Sustained-release hydrogel delivered effective local therapy in murine model
Longevity Analysis
Fibrosis and cellular senescence converge on the same upstream failure: mitochondria losing control of calcium flux at their interface with the endoplasmic reticulum. Correcting that interface — rather than suppressing downstream collagen output — reduced the senescent burden in skin fibroblasts, which positions organelle communication as a tractable target wherever tissue stiffening accompanies aging. The energy-generating machinery and regenerative capacity of a tissue are not separate problems, and a plant-derived compound with a defined binding residue offers a precise entry point into both.
Original published by Wiley Aging Cell, by Fei Wang, Ru Xing, Meijuan Xie, Yimin Qin, Yunchao Zhang, Dan Cao, Gu He, Xiaoyan Lyu .