MiR-30a-5p Alters Epidermal Terminal Differentiation during Aging by Regulating BNIP3L/NIX-Dependent Mitophagy

Abstract

Chronological aging is characterized by an alteration in the genes’ regulatory network. In human skin, epidermal keratinocytes fail to differentiate properly with aging, leading to the weakening of the epidermal function. MiR-30a is particularly overexpressed with epidermal aging, but the downstream molecular mechanisms are still uncovered. The aim of this study was to decipher the effects of miR-30a overexpression in the human epidermis, with a focus on keratinocyte differentiation. We formally identified the mitophagy receptor BNIP3L as a direct target of miR-30a. Using a 3D organotypic model of reconstructed human epidermis overexpressing miR-30a, we observed a strong reduction in BNIP3L expression in the granular layer. In human epidermal sections of skin biopsies from donors of different ages, we observed a similar pattern of BNIP3L decreasing with aging. Moreover, human primary keratinocytes undergoing differentiation in vitro also showed a decreased expression of BNIP3L with age, together with a retention of mitochondria. Moreover, aging is associated with altered mitochondrial metabolism in primary keratinocytes, including decreased ATP-linked respiration. Thus, miR-30a is a negative regulator of programmed mitophagy during keratinocytes terminal differentiation, impairing epidermal homeostasis with aging.

Mitochondrial dynamics and metabolism across skin cells: implications for skin homeostasis and aging

“…Depletion of NIX hampered epidermal maturation and disrupted the elimination of mitochondria, whereas the overexpression of NIX accelerated keratinocyte differentiation and led to premature mitochondrial fragmentation (Simpson et al, 2021). Furthermore, the expression of BNIP3, another mitophagy receptor highly expressed in the upper layers of the epidermis, decreases with chronological aging in the human epidermis reinforcing the idea that age-related dysfunction of mitophagy impacts epidermal homeostasis (Chevalier et al, 2022). Thus, the elimination of mitochondria by mitophagy seems to be less efficient in aged keratinocytes accompanied by reduced ATP production, suggesting that improper mitochondria dynamics could be involved in impaired cornification of old skin (Xiaoyun et al, 2017).…”

“…In contrast to keratinocytes located in the stratum spinosum, those within the stratum granulosum possess a higher quantity of mitochondria that are organized in a more compact mitochondrial network (Mellem et al, 2017). Apart from a consistently strong inter-individual variation in the number of mitochondria in proliferating keratinocytes, no age-associated differences in the number of mitochondria have been observed comparing cells isolated from young and old subjects in vitro (Chevalier et al, 2022), whereas mitochondria connectivity is decreased in keratinocytes from older individuals in comparison to younger ones (Mellem et al, 2017).…”

Chronological aging impacts abundance, function and microRNA content of extracellular vesicles produced by human epidermal keratinocytes

“…This was the case of miR-30a, for which the two strands -3p and -5p were enriched in aged keratinocytes EVs. We previously identified miR-30a as a key regulator of human epidermal aging: miR-30a is actually up-regulated in aged epidermis and this induction is at least partly responsible for age-related differentiation defects and cell death boost in human epidermis [ 9 , 28 ]. The fact that miR-30a-3p and 5p are carried by EVs and enriched in EVs from old cells suggests that aged keratinocytes could propagate their functional defects to surrounding cells by miR-30a secretion.…”

Extracellular vesicles in skin health, diseases, and aging

“…[51][52][53][54] Studies have revealed significant protein and miRNA alterations in EVs from senescent cells compared to controls, suggesting their involvement in wound healing, cell adhesion, and immune signaling pathways. 54,55,119 Hence, understanding EV contents and functions in skin aging is crucial. Targeting EV biogenesis and secretion may represent a promising strategy for alleviating senescence and mitigating the effects of aging on the skin.…”