NIX initiates mitochondrial fragmentation via DRP1 to drive epidermal differentiation

Simpson, Cory L.; Tokito, Mariko; Uppala, Rattapon; Sarkar, Mrinal K.; Guðjónsson, Jóhann E.; Holzbaur, Erika L.F.

doi:10.1016/j.celrep.2021.108689

Cited by 45 publications

(49 citation statements)

References 96 publications

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“…However, another work proposes a predominating role of mitochondrial-derived ROS in basal KCs as a signal to induce differentiation [ 41 ]. This is in line with a recent report showing that NIX, a transcription factor located in mitochondria, controls mitophagy and, in turn, KC differentiation, hence emphasizing the role of mitochondria in KC fate [ 42 ]. Thus, further work is required to clarify the relative contribution of glycolysis versus oxidative phosphorylation (OXPHOS) in the control of homeostatic processes in the epidermis.…”

Section: Metabolic Features Of Keratinocytes In Normal Skinsupporting

confidence: 91%

PPARdelta in Affected Atopic Dermatitis and Psoriasis: A Possible Role in Metabolic Reprograming

Blunder

Pavel

Minzaghi

et al. 2021

IJMS

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Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors expressed in the skin. Three PPAR isotypes, α (NRC1C1), β or δ (NRC1C2) and γ (NRC1C3), have been identified. After activation through ligand binding, PPARs heterodimerize with the 9-cis-retinoic acid receptor (RXR), another nuclear hormone receptor, to bind to specific PPAR-responsive elements in regulatory regions of target genes mainly involved in organogenesis, cell proliferation, cell differentiation, inflammation and metabolism of lipids or carbohydrates. Endogenous PPAR ligands are fatty acids and fatty acid metabolites. In past years, much emphasis has been given to PPARα and γ in skin diseases. PPARβ/δ is the least studied PPAR family member in the skin despite its key role in several important pathways regulating inflammation, keratinocyte proliferation and differentiation, metabolism and the oxidative stress response. This review focuses on the role of PPARβ/δ in keratinocytes and its involvement in psoriasis and atopic dermatitis. Moreover, the relevance of targeting PPARβ/δ to alleviate skin inflammation is discussed.

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Section: Metabolic Features Of Keratinocytes In Normal Skinsupporting

confidence: 91%

PPARdelta in Affected Atopic Dermatitis and Psoriasis: A Possible Role in Metabolic Reprograming

Blunder

Pavel

Minzaghi

et al. 2021

IJMS

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“…To confirm the regulation of BNIP3L by miR-30a in a more relevant system, we took advantage of an organotypic model of RHE generated from HPK overexpressing miR-30a. Using three different human donors, we showed that keratinocytes normally express BNI3PL in the granular layer of the epidermis (Figure 2A), in accordance with its described function in the degradation of mitochondria during the cornification (Simpson et al, 2021). Strikingly, the overexpression of miR-30a in keratinocytes induced a strong reduction of BNIP3L staining in the granular layer.…”

Section: Mir-30a-5p Abolishes Bnip3l Expression In the Granular Layer Of Rhesupporting

confidence: 67%

“…In the epidermis, autophagy is constitutively active in the granular layer, where nuclei are cleared, leading to the terminal differentiation (Akinduro et al, 2016). In addition, mitophagy, a specialized type of autophagy that targets mitochondria for elimination, is a key step to activate the terminal differentiation of keratinocytes, through the BNIP3/BNIP3L (also known as NIX) pathway (Monteleon et al, 2018;Moriyama et al, 2014;Simpson et al, 2021). Interestingly, autophagy is a recurrent biological pathway targeted by miR-30 family in others systems, especially in many types of cancers (Pourhanifeh et al, 2020;Yang et al, 2021;Zhu et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

MiR-30a-5p alters epidermal terminal differentiation during aging by regulating BNIP3L/NIX-dependent mitophagy

Chevalier

Rorteau

Ferraro

et al. 2021

Preprint

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Chronological aging is characterized by an alteration of 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 of 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 decrease 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.

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“…Upon phosphorylation, these receptors interact with phagophore proteins such as LC3 and Gabarap [ 189 , 191 , 196 ]. In the early stages of mitophagy, Bnip/Nix also promote the mitochondrial localization of Drp1, which would enhance fission and aid in Parkin recruitment, leading to mitophagy [ 197 , 198 , 199 ].…”

Section: Regulation Of Mitophagy In Musclementioning

confidence: 99%

Manifestations of Age on Autophagy, Mitophagy and Lysosomes in Skeletal Muscle

Triolo

Hood

2021

Cells

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Sarcopenia is the loss of both muscle mass and function with age. Although the molecular underpinnings of sarcopenia are not fully understood, numerous pathways are implicated, including autophagy, in which defective cargo is selectively identified and degraded at the lysosome. The specific tagging and degradation of mitochondria is termed mitophagy, a process important for the maintenance of an organelle pool that functions efficiently in energy production and with relatively low reactive oxygen species production. Emerging data, yet insufficient, have implicated various steps in this pathway as potential contributors to the aging muscle atrophy phenotype. Included in this is the lysosome, the end-stage organelle possessing a host of proteolytic and degradative enzymes, and a function devoted to the hydrolysis and breakdown of defective molecular complexes and organelles. This review provides a summary of our current understanding of how the autophagy-lysosome system is regulated in aging muscle, highlighting specific areas where knowledge gaps exist. Characterization of the autophagy pathway with a particular focus on the lysosome will undoubtedly pave the way for the development of novel therapeutic strategies to combat age-related muscle loss.

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NIX initiates mitochondrial fragmentation via DRP1 to drive epidermal differentiation

Cited by 45 publications

References 96 publications

PPARdelta in Affected Atopic Dermatitis and Psoriasis: A Possible Role in Metabolic Reprograming

PPARdelta in Affected Atopic Dermatitis and Psoriasis: A Possible Role in Metabolic Reprograming

MiR-30a-5p alters epidermal terminal differentiation during aging by regulating BNIP3L/NIX-dependent mitophagy

Manifestations of Age on Autophagy, Mitophagy and Lysosomes in Skeletal Muscle

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