Chronic wounds, such as venous ulcers, affect many elderly and are associated with substantial morbidity and costs for society. The treatment of today focus on the fact that the wounds are hypoxic, but oxygen-delivery therapy alone in chronic wounds is often insufficient. Importantly, wound healing is highly energy dependent and therefore dependent on sufficient ATP-production. ATP is a metabolic energy currency and mitochondria is responsible for 90% of ATP production. The ATP is produced by mitochondria through oxidative phosphorylation. The ATP synthesis is driven by the electron liberation from reduced substrates in the mitochondrial respiratory chain.
Mitochondrial ATP synthesis capacity is to a large extent dependent on mitochondrial morphology and dynamics termed mitochondrial dynamics. The mitochondria architecture is determined by a balance between fusion (elongated mitochondria) and fission (fragmented mitochondria). Mitochondrial fusion is when the mitochondria merge into larger structures, which have a high coupling between consumed oxygen and generated ATP. The contrary process is mitochondria fission, where smaller mitochondria are produced and they present lower coupling efficiency, but less ATP production. Mitochondrial fusion, fission, and mitophagy (elimination of mitochondria through autophagosomes) are an essential axis of mitochondrial quality control. Defects in either fusion or fission limit mitochondrial motility, decrease energy production and increase oxidative stress, thereby promoting cell dysfunction and death. The two opposing processes, fusion and fission, are controlled by evolutionarily conserved large GTPases that belong to the dynamin family of proteins. In mammalian cells, mitochondrial fusion is regulated by mitofusin-1 and -2 (MFN-1/2) and optic atrophy 1 (OPA1), whereas mitochondrial fission is controlled by dynamin-1-related protein, Drp1 and its mitochondrial adaptors such as Fis1, Mff, and MIEF.
In resume, 1) The wound healing process require a high amount of ATP, 2) The principal ATP producer in the cell is the mitochondria, 3) Fragmented mitochondria produce less ATP amount and 4) Defects in mitochondrial dynamics can promote cellular dysfunction and death. We hypothesize that in chronic skin wounds mitochondria are more fragmented and that this contributes to poor healing. Correcting this dysfunction may promote healing. A master student would contribute to part of this project as outlined below.
Aim 1: To determine mitochondrial mass in human chronic ulcer subject
Aim2: To characterize mitochondrial morphology in human chronic ulcer subjects
Aim3: To characterize proteins related to mitochondrial dynamics in human chronic ulcer subjects