Keratin-dependent regulation of mitochondria in keratinocytes and mouse epidermis

• Applicant: Professor Dr. Thomas Magin
• Subject Area: Cell Biology
• Term: from 2010 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 194376116

• Final Report Year: 2021

Final Report Abstract

In this project, we investigated the role of keratins in mitochondrial dynamics and physiology, using keratinocytes which lack the entire keratin cytoskeleton following deletion of keratin gene clusters, in comparison to normal control an rescue cells that re-express a single keratin pair. In addition, we investigated the interplay of keratins and mitochondria in EBS and normal human keratinocytes. The comparative analysis of keratin-deficient and WT mouse keratinocytes and of human EBS and normal keratinocytes revealed a hitherto unknown role of keratins in mitochondrial positioning, dynamics and activity. In the absence of keratins, mitochondria were hyperfused. We showed that keratins modulate cellular redox homeostasis, which affects mitochondrial morphology and function partially via Drp1 translocation to mitochondria. This suggests that a crosstalk between keratins and mitochondria might adapt ROS signaling and metabolism to maintain epidermal integrity during tissue homeostasis, upon barrier defects, blistering skin disease and wounding. Our analysis of the EBS-associated K14R125C mutation revealed an impaired mitochondrial activity in primary and immortalized EBS keratinocytes which may be relevant for epidermal physiology, including barrier formation and diseases resulting in inflammation following barrier defects, such as atopic dermatitis.

Publications

• Lessons from Animal Models of Cytoplasmic Intermediate Filament Proteins. Subcell Biochem. 2017;82:171-230
  Bouameur JE, Magin TM
  
• Keratins Regulate p38MAPK-Dependent Desmoglein Binding Properties in Pemphigus. Front Immunol. 2018 Mar 19;9:528
  Vielmuth F, Walter E, Fuchs M, Radeva MY, Buechau F, Magin TM, Spindler V, Waschke J
  
• Mouse Keratinocytes Without Keratin Intermediate Filaments Demonstrate Substrate Stiffness Dependent Behaviors. Cell Mol Bioeng. 2018 May 2;11(3):163-174
  Zarkoob H, Chinnathambi S, Halberg SA, Selby JC, Magin TM, Sander EA
  
• Keratin defects trigger the itch- inducing cytokine thymic stromal lymphopoietin through amphiregulin-epidermal growth factor receptor signaling. J Allergy Clin Immunol. 2019 Dec;144(6):1719-1722.e3
  Scheffschick A, Kiritsi D, Magin TM
  
• A dominant vimentin variant causes a rare syndrome with premature aging. Eur J Hum Genet. 2020 Sep;28(9):1218- 1230
  Cogné B, Bouameur JE, Hayot G, Latypova X, Pattabiraman S, Caillaud A, Si-Tayeb K, Besnard T, Küry S, Chariau C, Gaignerie A, David L, Bordure P, Kaganovich D, Bézieau S, Golzio C, Magin TM, Isidor B
  
• An intact keratin network is crucial for mechanical integrity and barrier function in keratinocyte cell sheets. Cell Mol Life Sci. 2020 Nov;77(21):4397-4411
  Karsch S, Büchau F, Magin TM, Janshoff A
  
• Disease-associated keratin mutations reduce traction forces and compromise adhesion and collective migration. J Cell Sci. 2020 Jul 29;133(14):jcs243956
  Fujiwara S, Deguchi S, Magin TM
  
• Epidermolysis Bullosa Simplex Keratinocytes Show Disturbed Mitochondrial Positioning and Activity. J Invest Dermatol. 2020 Jul;140(7):1438-1442.e5
  Vetter A, Jahn K, Bouameur JE, Kiritsi D, Magin TM
  
• Epidermolysis bullosa. Nat Rev Dis Primers. 2020 Sep 24;6(1):78
  Bardhan A, Bruckner-Tuderman L, Chapple ILC, Fine JD, Harper N, Has C, Magin TM, Marinkovich MP, Marshall JF, McGrath JA, Mellerio JE, Polson R, Heagerty AH
  
• Old mitochondria accumulate in pachyonychia congenita. Br J Dermatol. 2020 Mar;182(3):529-530
  Vetter A, Magin TM