Impaired Mitophagy-Induced Apoptosis of Gingival Fibroblasts Exacerbates Diabetic Periodontitis Via THBS-1/CD36-Dependent Macrophage Activation

Jan 14, 2026Inflammation

Poor Removal of Damaged Cell Parts Causes Gum Cell Death That Worsens Diabetic Gum Disease Through Activation of Immune Cells

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Abstract

Single-cell sequencing of diabetic gingival tissues revealed significant apoptotic activation of gingival fibroblasts.

Apoptotic gingival fibroblasts are linked to mitochondrial dysregulation in diabetic periodontitis.
Inflammation and metabolic stress disrupt pathways that maintain mitochondrial health, leading to excess reactive oxygen species.
Defective mitophagy is induced by these stressors, contributing to the progression of diabetic periodontitis.
Apoptotic fibroblasts release thrombospondin-1 (THBS-1), which activates macrophages via the CD36 receptor, promoting inflammation.
Gene silencing experiments confirm the role of THBS-1 and CD36 in mediating immune activation in this context.
Therapeutic strategies targeting enhanced mitophagy and the THBS-1/CD36 pathway could potentially alleviate inflammation and tissue damage.

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Diabetic periodontitis (DPD) is a severe inflammatory complication characterized by accelerated destruction of periodontal tissues and dysregulated immune responses. Gingival fibroblast (GF)-macrophage interactions drive DPD progression, but the mechanisms linking hyperglycemia, mitochondrial dysfunction, and immune activation remain unclear. Single-cell sequencing analysis of diabetic gingival tissues revealed significant apoptotic activation of GFs, closely linked to mitochondrial dysregulation. Inflammation and metabolic stress disrupt mitochondrial quality-control pathways and promote the overproduction of reactive oxygen species, inducing defective mitophagy. Crucially, apoptotic GFs secrete thrombospondin-1 (THBS-1), which binds to the CD36 receptor on the surface of macrophages, triggering NF-κB-mediated M1 polarization and pro-inflammatory cytokine production. Molecular modelling demonstrated a high-affinity interaction between THBS-1 and CD36. Gene silencing of THBS-1 in GFs or CD36 in macrophages effectively inhibited these changes, confirming the specificity of this cellular crosstalk mechanism. These findings together indicate mediation of hyperglycemia-induced mitochondrial dysfunction through the promotion of GF apoptosis and subsequent THBS-1/CD36/NF-κB-signaling-dependent macrophage activation. Thus, enhanced mitophagy and modulation of the THBS-1/CD36 axis are promising therapeutic strategies to break the self-perpetuating cycle of inflammation and tissue destruction in DPD.

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Impaired Mitophagy-Induced Apoptosis of Gingival Fibroblasts Exacerbates Diabetic Periodontitis Via THBS-1/CD36-Dependent Macrophage Activation

Abstract

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