Circulating cell-free mitochondrial DNA in diabetes mellitus: Current insights and unexplored frontiers

Abstract

The role and significance of circulating cell-free mitochondrial DNA (ccf-mtDNA)—small fragments of mitochondrial DNA present in plasma—are becoming increasingly clear in various diseases. The release of mtDNA into the plasma results from mitochondrial dysfunction, cell death, and NETosis, all of which are elevated in diabetes and its complications. Due to its resemblance to pathogenic DNA, mitochondrial DNA can activate several immunological pathways, leading to inflammation—a key factor in diabetes and its complications. Studies reveal a significant overlap between the immunological pathways involved in diabetes and those triggered by ccf-mtDNA. Thus, ccf-mtDNA may play a crucial role in the pathophysiology of diabetes and its complications, making it a potential diagnostic, prognostic, and therapeutic target. This review aims to summarize research findings on the role of ccf-mtDNA in diabetes, including gestational diabetes and related complications. Most studies have focused on type 2 diabetes, whereas research on ccf-mtDNA in other forms, including type 1 diabetes, remains limited. By synthesizing these insights, we seek to clarify the role of ccf-mtDNA in diabetes and identify gaps for future research.