Therapeutic Lithium Enhances Klotho Expression and Mitochondrial Size and Branching in Human Cardiac Fibroblasts...

Emerging studies suggest that lithium might be cardioprotective. Although studies have suggested that lithium improves mitochondrial dysfunction, promotes antiaging processes, and reduces cardiac fibrosis, whether lithium modulates Klotho, an antiaging protein, and mitochondrial morphology in human cardiac fibroblasts remains unclear. This study investigated the effects of therapeutic lithium on Klotho expression and mitochondrial morphology in human cardiac fibroblasts and underlying mechanisms.

We conducted microRNA sequencing, pathway enrichment analysis, mitochondrial morphology assessment, real-time reverse-transcription polymerase chain reaction, western blotting, and migration assay upon human cardiac fibroblasts and myocardial tissues of rats subjected to mania model.

Transcriptomic analysis of myocardial tissues from rats subjected to mania model unveiled that the significantly enriched pathways targeted by lithium were related to mitochondrial function. Mitochondrial morphology assessment showed that human cardiac fibroblasts treated with LiCl (1.0 mmol/L) for 48 hours exhibited greater mitochondrial area, perimeter length, and degree and length of branching than did control fibroblasts. Additionally, the messenger RNA and protein expression levels of Klotho were upregulated in human cardiac fibroblasts treated with LiCl (1.0 mmol/L) for 48 hours compared with control fibroblasts, whereas the levels of phosphorylated nuclear factor-kappa B (NF-κB) p65 were downregulated. Furthermore, human cardiac fibroblasts treated with the combination of LiCl (1.0 mmol/L) and Bay 11-7802 (3 μM) exhibited similar migration ability and mitochondrial size and branching relative to LiCl (1.0 mmol/L)-treated fibroblasts.

Lithium at a therapeutic concentration enhances Klotho expression and mitochondrial size and branching in human cardiac fibroblasts probably through NF-κB inhibition.