MPZL3 is a novel, therapeutically targetable mitochondrial regulator of human sebaceous gland homeostasis and function

Summary: Abstract Body: Both, PPARg and the mitochondrial protein, Myelin Protein Zero-like 3 (MPZL3), are known regulators of murine sebaceous gland (SG) homeostasis, while MPZL3 GKO and PPARg KO mice show a similar SG phenotype. Yet, the function of MPZL3 in human SG physiology and if PPARg signaling is upstream or downstream of MPZL3 remain unknown. To clarify this, we have co-administered the PPARg agonist, AGED, with MPZL3 siRNA or non-targeting oligos (NTO) in human SG organ culture. MPZL3 knockdown (KD) ex vivo significantly increased the % of PPARg+ sebocytes, the differentiation of Blimp1+ sebocyte progenitors, and stimulated the production of neutral lipids. Co-administration of AGED with NTO significantly reduced the expression of MPZL3 within SGs, which was further reduced when siMPZL3 was co-administered with AGED, suggesting that PPARg is upstream of MPZL3 and negatively regulates its expression. The % of PPARg+ cells in the central and peripheral zone of SGs was increased in SGs treated with siMPZL3+AGED compared to NTO+AGED. Thus, MPZL3 signaling may also be part of a negative feedback loop that downregulates PPARg expression. Moreover, the % of proliferative sebocytes in the SG’s peripheral zone is significantly reduced in siMPZL3+AGED compared to NTO+AGED-treated SGs, indicating that sebocyte differentiation is more prominent in when MPZL3 is silenced. Lipid/sebum production ex vivo was also significantly enhanced after MPZL3 silencing in the presence of PPARg stimulation, as shown by increased SG protein expression of perilipin-2 and fatty acid synthase expression. Our study identifies MPZL3 as a novel mitochondrial regulator downstream of PPARg that negatively controls human SG function and lipid production. Therefore, MPZL3 agonists deserve to be explored as therapeutics for disorders characterized by seborrhea and/or SG hyperplasia. Kazi Taheruzzaman², Aysun Akhundlu², Takahiro Suzuki^{2, 3}, Jennifer Gherardini¹, Tongyu C. Wikramanayake², Jeremy Cheret^{1, 2}, Ralf Paus^{1, 2} 1. CUTANEON-Skin&Hair Innovations GmbH, Hamburg&Berlin, Germany. 2. Dermatology, University of Miami Miller School of Medicine, Miami, FL, United States. 3. Dermatology, Hamamatsu Ika Daigaku Igakubu Fuzoku Byoin, Hamamatsu, Shizuoka Prefecture, Japan. Translational Studies: Cell and Molecular Biology