Kindlin-2 functional restoration through methylmalonic acid clearance by Coenzyme A counteracts osteoporosis.

Xuling Li, Guixing Ma, Fen Wang, Zhen Ding, Yong Chen, Siyuan Cheng, Wei Pang, Litong Chen, Huiling Cao

Department of Biochemistry, SUSTech Homeostatic Medicine Institute, School of Medicine, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Key University Laboratory of Metabolism and Health of Guangdong, Southern University of Science and Technology, Shenzhen 518055, China. · pubmed

Paper

Abstract

Old blood can induce senescence in young mice, yet the underlying mechanisms remain unclear. Here, we demonstrate that non-protein components (NP) of aged human serum (ONP) induce skeletal aging in young mice, with methylmalonic acid (MMA) identified as a key driver capable of independently recapitulating the skeletal aging phenotypes observed in ONP-treated mice. Photoaffinity labeling confirms Kindlin-2 as a direct intracellular MMA receptor. MMA binds directly to Kindlin-2 via a positively charged motif in its UBL domain, promoting Kindlin-2 ubiquitination and degradation, which accelerates skeletal aging. Notably, endogenous MMA scavenger coenzyme A (CoA), a clinically approved molecule, effectively reverses MMA- and ONP-induced skeletal aging. Furthermore, CoA treatment effectively protects against skeletal aging and bone mass loss in aged or estrogen-deficient mouse models. Our study establishes MMA as a central aging factor and Kindlin-2 as its intracellular receptor, offering a potential therapeutic strategy for age-related diseases, such as osteoporosis.

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Research summary

Methylmalonic acid (MMA) is identified as a key driver of skeletal aging, and its clearance via Coenzyme A can reverse age-related bone loss. This paper is relevant as it addresses a potential root cause of aging by identifying MMA's role in skeletal aging and proposing a therapeutic strategy to counteract its effects.

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