Track

Clinical Studies

Abstract

Background: Peripheral Artery Disease (PAD) affects >200 million patients. Atherosclerosis in PAD produces ischemic damage, characterized by oxidative and mitochondrial damage. Compromised wound healing at weight-bearing regions of the foot is a leading cause of morbidity and mortality in PAD. Damaged mitochondria contribute to impaired cellular function and delayed wound healing. Cells depend on mitophagy to remove damaged mitochondria. However, studies of mitophagy in the skin of PAD are very limited. This project is the first to quantitatively evaluate epidermal mitophagy in PAD.

Methods: 3 foot skin specimens from non-PAD organ donors (weight-bearing regions) and 7 from amputated PAD legs (4 from weight-bearing regions and 3 from non-weight-bearing regions) were collected. Immunofluorescence was performed to quantify epidermal autophagy (LC3) and mitophagy (PINK1). PINK1/LC3 ratio is used to reflect the mitophagy portion of total autophagy.

Results: While autophagy was lower in the basal layer, epidermal mitophagy distributes relatively evenly. In weight-bearing regions of the foot, epidermal mitophagy (PINK1) was lower in PAD, compared to non-PAD (27449±3254 gsu vs. 14271±514 gsu, p<0.05). There was no significant difference in LC3 or PINK1/LC3 ratio. Although all from end-stage PAD feet, non-weight-bearing regions exhibited higher epidermal PINK1 (43111±6394 gsu vs. 27449±3254 gsu, p<0.01) and PINK1/LC3 ratio (5.98±0.88 vs. 1.43±0.78, p<0.005), than weight-bearing regions.

Conclusions: Epidermal mitophagy is compromised in the weight-bearing foot skin of end-stage PAD patients, which might contribute to accumulated mitochondrial damage and poor wound healing. Future therapies targeting mitophagy may improve skin health and reduce the morbidity and mortality of PAD patients.