Mitochondria & peroxisomes: new targets in AD

Atopic dermatitis (AD) is a chronically relapsing inflammatory skin disease with a high prevalence worldwide (affecting 10-30% of children and 2-10% of adults) that imposes a huge socioeconomic burden. The quality of life of AD patients is seriously impacted because of itching and scratching, which, in severe cases, can cause sleep deprivation, food limitation, pain, bleeding in children, and depression in adults. Importantly, AD is the initial step in the so-called atopic march, where an average of 40% of children with AD goes on to develop asthma and/or allergic rhinitis later in life. AD is a complex disease whose full pathogenesis has not yet been elucidated because of disease heterogeneity and, in most cases, its early age of onset (<1 year), which precludes invasive studies for ethical reasons. However, epidermal barrier impairment is considered the pathologic cornerstone of AD, as it is observed in all AD patients. Moreover, there is a consensus that abnormal epidermal barrier function is the driving force in the development of skin inflammation, which, in turn, further weakens the barrier and perpetuates a vicious pathological cycle. Compromised epidermal barrier function can result from genetic alterations in certain genes related to epidermal structure. This leads to excessive water loss through the skin, which can be life-threatening owing to dehydration and perturbation of body-temperature homeostasis. In response, compensatory mechanisms are initiated by the skin to reduce the loss of water and heat. These mechanisms include epidermal cell renewal. However, because the barrier defect is likely genetically caused, complete restoration of the barrier is never achieved, thereby leading to epidermal cell hyper-proliferation. The latter condition creates energetic stress in epidermal cells because of the high energy-demand of cell proliferation. Thus, we hypothesize that mitochondria and peroxisomes, as the cells major energy producers, are hyperactivated in AD skin. Moreover, as a pernicious side effect of this enhanced mitochondrial and peroxisomal metabolism, pro-oxidant molecules are produced and accumulate in the skin where they drive inflammation. Therefore, the objectives of this project are: 1) to decipher the role of mitochondria and peroxisomes in AD, and 2) based on our findings in objective 1, to test in pre-clinical trials new therapeutic strategies aimed at stopping the course of AD. To date, the role of abnormal metabolism in mitochondria and peroxisomes has never been studied in inflammatory skin diseases, whereas it represents a rich source of new potential therapeutic targets.

Atopic dermatitis (AD) is a chronically relapsing inflammatory skin disease with a high prevalence worldwide (affecting 10-30% of children and 2-10% of adults) that imposes a huge socioeconomic burden. The quality of life of AD patients is seriously impacted because of itching and scratching, which, in severe cases, can cause sleep deprivation, food limitation, pain, bleeding in children, and depression in adults. Importantly, AD is the initial step in the so-called 'atopic march', where an average of 40% of children with AD goes on to develop asthma and/or allergic rhinitis later in life. AD is a complex disease whose full pathogenesis has not yet been elucidated because of disease heterogeneity and, in most cases, its early age of onset (<1 year), which precludes invasive studies for ethical reasons. However, epidermal barrier impairment is considered the pathologic cornerstone of AD, as it is observed in all AD patients. Moreover, there is a consensus that abnormal epidermal barrier function is the driving force in the development of skin inflammation, which, in turn, further weakens the barrier and perpetuates a vicious pathological cycle. Compromised epidermal barrier function can result from genetic alterations in certain genes related to epidermal structure. This leads to excessive water loss through the skin, which can be life-threatening owing to dehydration and perturbation of body-temperature homeostasis. In response, compensatory mechanisms are initiated by the skin to reduce the loss of water and heat. These mechanisms include epidermal cell renewal. However, because the barrier defect is likely genetically caused, complete restoration of the barrier is never achieved, thereby leading to epidermal cell hyper-proliferation. The latter condition creates energetic stress in epidermal cells because of the high energy-demand of cell proliferation. In this project we have demonstrated that mitochondria and peroxisomes, as the cell's major energy producers, are hyperactivated in AD skin. Moreover, as a pernicious side effect of this enhanced mitochondrial and peroxisomal metabolism, pro-oxidant molecules are produced and accumulate in the skin where they drive inflammation. Pre-clinical trials in skin organotypic cultures (organoids) and mice showed promising therapeutic effects to alleviate AD symptoms. This project allowed to report, for the first time, the role of abnormal metabolism in mitochondria and peroxisomes in AD pathogenesis, which represents a rich source of new potential therapeutic targets.