Study identifies mitochondrial transporter SLC25A12 as therapeutic target for skeletal muscle aging and cuproptosis

A cross-species study published in Biology Direct reports that SLC25A12 mitigates myoblast senescence and cuproptosis-related changes, identifying it as a potential therapeutic target for sarcopenia.

Integrating transcriptomic analysis from human sarcopenia datasets and 24-month-old naturally aging mice, researchers identified the mitochondrial gene SLC25A12 as consistently downregulated in aged skeletal muscle.

In vitro, SLC25A12 overexpression in C2C12 myoblasts attenuated D-galactose-induced senescence, preserved mitochondrial membrane potential, rescued ATP production, and restored the balance of mitochondrial dynamics.

Under copper stress, elevated SLC25A12 levels limited mitochondrial copper accumulation, suppressed dihydrolipoamide S-acetyltransferase (DLAT) oligomerization, and restored myoblast proliferation, while SLC25A12 knockdown exacerbated these cuproptosis-related phenotypes.

In silico single-cell simulations using the Geneformer model, combined with in vitro experiments, demonstrated that SLC25A12 partially restores suppressed PI3K/AKT signaling and MYF5 expression in senescent conditions, a rescue that was blocked by the PI3K inhibitor LY294002.

Sarcopenia represents a global healthcare challenge, affecting approximately 10% of individuals over 60 years old and costing the United States healthcare system over $18.5 billion annually, yet it lacks specific pharmacological therapies.

Mitochondrial dysfunction and cellular senescence are tightly linked to sarcopenia pathogenesis, but identifying conserved, cross-species validated therapeutic targets remains a major bottleneck.

By demonstrating that SLC25A12 links the malate-aspartate shuttle to copper homeostasis, the study outlines a novel target pathway that addresses both bioenergetic deficits and cuproptosis in skeletal muscle aging.

The identification of SLC25A12 adds a novel, translationally conserved target to the sarcopenia and muscle preservation landscape.

The study's successful application of the 12-layer Geneformer model for in silico perturbation prediction validates the commercial trend of using generative AI platforms to streamline target discovery in cellular aging.

Biotech companies focused on muscle preservation and mitochondrial restoration during aging may leverage these findings to support the rationale for therapeutics targeting metabolic and senescent pathways in skeletal muscle.

Subsequent in vivo validation using genetic overexpression or targeted pharmacological activators of SLC25A12 in aging animal models to evaluate changes in muscle mass and grip strength.

Further characterization of the structural or molecular mechanisms by which the malate-aspartate shuttle interacts with mitochondrial copper transport systems.