Network Analysis Identifies Mitochondrial Regulation of Epidermal Differentiation by MPZL3 and FDXR

Abstract

SUMMARY Current gene expression network approaches commonly focus on transcription factors (TFs), biasing network-based discovery efforts away from potentially important non-TF proteins. We developed proximity analysis, a network reconstruction method that uses topological constraints of scale-free small-world biological networks to reconstruct relationships in eukaryotic systems, independent of subcellular localization. Proximity analysis identified MPZL3 as a highly connected hub that is strongly induced during epidermal differentiation. MPZL3 was essential for normal differentiation, acting downstream of p63, ZNF750, KLF4 and RCOR1, each of which bound near the MPZL3 gene and controlled its expression. MPZL3 protein localized to mitochondria, where it interacted with FDXR, which was itself also found to be essential for differentiation. Together, MPZL3 and FDXR increased reactive oxygen species (ROS) to drive epidermal differentiation. ROS-induced differentiation is dependent upon promotion of FDXR enzymatic activity by MPZL3. ROS induction by the MPZL3 and FDXR mitochondrial proteins is therefore essential for epidermal differentiation.

PFKFB3, a Direct Target of p63, Is Required for Proliferation and Inhibits Differentiation in Epidermal Keratinocytes

“…Keratinocytes from these mice are constitutively glycolytic and exhibited impaired differentiation both in vitro and in vivo . Further, we and others have shown that mitochondrial generation of reactive oxygen species promotes keratinocyte differentiation (Bhaduri et al, 2015, Hamanaka et al, 2013). These observations, along with the present results, suggest that a switch from glycolytic to oxidative metabolism promotes keratinocyte differentiation.…”

Ferredoxin reductase is critical for p53-dependent tumor suppression via iron regulatory protein 2

“…Additionally, through interaction with MPZL, FDXR plays a role in ROS-induced epidermal cell differentiation via mitochondria (Bhaduri et al 2015). Here, we found that, by modulating RSL3-and Erastin-induced ferroptosis, FDXR plays a role in p53-dependent ferroptosis (Supplemental Fig.…”

“…Through interaction with the Fhit tumor suppressor, FDXR modulates apoptosis induced by Fhit (Trapasso et al 2008). Through interaction with MPZL, a mitochondrial protein and reactive oxygen species (ROS) inducer, FDXR regulates epidermal cell differentiation via mitochondria (Bhaduri et al 2015). FDXR is also found to be the most consistent internal biodosimetry marker in the peripheral blood following radiation therapy (Abend et al 2016;Edmondson et al 2016).…”

Loss of MPZL3 function causes seborrhoeic dermatitis‐like phenotype in mice

“…The SD-like clinical and histologic features in the Mpzl3 −/− mice also resemble those in patients carrying a frame-shift mutation in ZNF750, a key regulator of epidermal differentiation and a transcriptional activator of the MPZL3 gene [2, 6]. Therefore, we conclude that the ZNF750/MPZL3 pathway plays a critical role in the pathogenesis of SD, and a better understanding of skin inflammation and barrier restoration in the Mpzl3 −/− mice will provide insight into the pathogenesis and treatment/prevention of recurrent SD.…”

“…Interestingly, these mice also developed early onset skin inflammation with dandruff-like flakes [4]. Importantly, ZNF750 was recently shown to directly bind to MPZL3 promoter and activate its transcription in cultured human keratinocytes [6]. Therefore, Mpzl3 knockout mice can serve as a useful model to understand SD pathogenesis caused by ZNF750 dysfunction.…”