Melatonin ameliorates inflammation-induced mitochondrial dysfunction and cementoblastic differentiation in cells by regulating the METTL3/LINC01444/HSPD1 axis.

Inflammation-induced mitochondrial dysfunction functionally impairs periodontal ligament stem cells (PDLSCs) and hinders their therapeutic efficacy in periodontal regeneration. Melatonin, a mitochondrion-targeted molecule, is considered a promising anti-inflammatory agent in therapeutics, but whether melatonin protects PDLSC cementoblastic differentiation against inflammation-induced damage and the underlying mechanisms of this function remain unclear. This study confirmed that melatonin rescued PDLSC cementoblastic differentiation under inflammatory conditions and that melatonin-induced recovery was linked to ameliorated mitochondrial function in cells. Next, through lncRNA microarray analysis, mass spectrometry and functional studies, an interaction between LINC01444 and HSPD1 was identified as a mechanism mediating these melatonin-induced mitochondrial changes. In this context, suppressing LINC01444 was found to increase the total and cytoplasmic HSPD1 protein levels, and in turn, mitochondrial function improved. We further revealed the upstream mechanism by which melatonin inhibited the m6A modification of LINC01444, thereby decreasing its stability and expression. Our data indicate that LINC01444 is a key target involved in the restorative effects of melatonin on cellular mitochondrial function and cementoblastic differentiation. Melatonin inhibits LINC01444 m6A modification to maintain its stability and expression, and prevents LINC01444 from interacting with HSPD1 to exert its damaging effects on PDLSCs.