Emerging frontiers in the mitochondrial regulation of dendritic cell biology

Dendritic Cells are central players of our immune system, linking innate sensing to adaptive immunity through antigen presentation and T cell priming. Beyond transcriptional and cytokine-based regulation, mitochondria are emerging as potential regulators of Dendritic Cell biology. While still in its infancy, evidence is accumulating that mitochondrial pathways affect Dendritic Cell differentiation; that mitochondrial remodeling and bioenergetic rewiring underpin Dendritic Cell maturation and activation in response to pathogenic and inflammatory stimuli and that shifts in mitochondrial and redox dynamics, reactive oxygen species production and mitochondrial DNA release coincide with Dendritic Cell activation and co-stimulatory molecule expression. Mitochondria are furthermore involved in regulating Dendritic Cell migration by influencing cellular metabolism and cytoskeletal dynamics and support the antigen processing and presentation machinery, thereby dictating the quality of the initiated T cell response. Importantly, mitochondrial checkpoints also regulate Dendritic Cell survival, balancing immune activation with timely cell death to preserve immune homeostasis. While the exact pathways of mitochondrial regulation are just beginning to be understood, disruptions in these programs can be far reaching. During aging, progressive mitochondrial dysfunction has been associated with impaired Dendritic Cell differentiation, diminished antigen presentation and impaired T cell responses. Similar defects have been observed in chronic diseases and cancer, leading us to hypothesize that genetic disorders linked to mitochondrial dysfunction also lead to defects in Dendritic Cell biology, impacting clinical symptoms such as immune dysregulation, heightened infection risk and inappropriate chronic inflammation. Therefore, in this review we have summarized the emerging roles of mitochondrial regulation in Dendritic Cell biology and discuss therapeutic opportunities to restore immune competence by targeting mitochondrial and redox pathways in settings of Dendritic Cell dysfunction. These insights aim to encourage further research into these topics and propose targeted metabolic reprogramming as a new therapeutic strategy for healthy ageing and chronic disease management.