Psoriasis-like skin inflammation drives an elongated mitochondrial network marked by functional failure in keratinocytes.
Abstract
Background
Psoriasis is characterized by a pathogenic, hyperproliferative state of keratinocytes. While inflammation is known to drive this proliferation and induce metabolic reprogramming to regulate immune effector functions, the specific mitochondrial and metabolic alterations in keratinocytes during psoriatic inflammation remain poorly understood.
Objective
To determine how cutaneous inflammation dynamically modulates mitochondrial networks and bioenergetics within the epidermal compartment, and to evaluate the metabolic consequences of disrupting this morphology.
Methods
Using a standardized mouse model of psoriasis-like inflammation, keratinocyte culture and in silico human psoriatic samples, we assessed mitochondrial health. We analyzed mitochondrial membrane potential and quantified metabolites associated with the Tricarboxylic Acid (TCA) cycle. Additionally, we evaluated the expression and activity of mitochondrial fusion and structural synthesis machinery in mouse tissues.
Results
Imiquimod-driven inflammation induces mitochondrial dysfunction, marked by reduced membrane potential and suppression of key TCA cycle intermediates. Rather than undergoing fragmentation, psoriatic keratinocytes exhibit a shift toward fused network state marked by Pgc-1α presence. Pharmacological disruption of this architecture via Mdivi-1 fails to restore function and ameliorate disease progression in vivo; instead, it increases reactive oxygen species production and acts synergistically with IL-17A to robustly amplify pro-inflammatory cytokine secretion.
Conclusion
This study shows that an elongated, fused mitochondrial network architecture is a feature of the epidermal compartment under chronic psoriatic inflammation. Furthermore, our findings demonstrate that promoting this structural state via mitochondrial division inhibitors does not improve psoriasis-like inflammation in vivo but rather exacerbates cellular oxidative stress and sustains skin inflammation.