Multi-omics analysis identifies mitochondrial dysfunction in CD83+ macrophages as a key event in diabetic peripheral neuropathy progression

BACKGROUND: Diabetic peripheral neuropathy (DPN) is a debilitating diabetic complication marked by progressive nerve fiber loss and dysfunction. While extensive studies have focused on the onset of DPN, the mechanisms underlying its progression remain poorly understood. Once DPN progression occurs, it can render nerve damage irreversible and make treatment more challenging. Emerging evidence suggests that immune and mitochondrial metabolic dysregulation play critical roles in disease exacerbation, yet the specific cell subtype and molecular mediators driving DPN progression have not been systematically identified. METHODS: Constructed a progressive DPN mouse model for bulk sequencing to explore progression-related mechanisms. Integrated Scissor and multi-omics analyses identified key cell subtypes and hub genes. TIMM23's role in DPN progression and mitochondrial function was validated in vitro in bone marrow-derived macrophages (BMDMs) and in vivo via adeno-associated virus-mediated overexpression. RESULTS: Mitochondrial metabolic dysfunction is a potential core mechanism underlying the progression of DPN. CD83+ macrophages were identified as the most prominent and specific subset associated with mitochondrial dysfunction and the DPN progression. Accordingly, we constructed a progressive DPN-related mitochondrial score, which enabled quantitative evaluation of DPN progression, inflammation, and immune infiltration. In vitro, high-glucose or high-fat intervention in BMDMs resulted in reduced expression of TIMM23. TIMM23 overexpression increased ATP production and mitochondrial mass, while reducing reactive oxygen species. In vivo, TIMM23 overexpression in the sciatic nerve improved nerve conduction velocity and nociceptive responses. CONCLUSION: This study highlights the first discovery of CD83+ macrophages in DPN progression and identifies TIMM23 as a potential diagnostic and therapeutic marker.