583 Hair cycle regulation by a mitochondrially localized protein: Is MPZL3 a central component of the elusive hair cycle clock?

Abstract

Hair follicles (HFs) undergo cycles of growth (anagen), regression (catagen) and relative quiescence (telogen). The intrinsic and autonomous molecular oscillator system that drives the hair cycle (HC)—the “hair cycle clock (HCC)”—remains incompletely understood. In this study, we present evidence that Myelin Protein Zero-like 3 (MPZL3), a multifunctional nuclear-encoded protein localized in mitochondria and is primarily known to be involved in epidermal differentiation, also regulates the murine HCC. In the absence of functional MPZL3, Mpzl3 global knockout mice commence HF cycling with retarded first catagen-telogen transition after normal postnatal HF morphogenesis. However, they then display strikingly accelerated HF cycling, i.e., a precocious telogen-anagen transition during the second HC, compared to controls, suggesting that MPZL3 normally functions as an inhibitor of anagen entry. We also show that intrafollicular MPZL3 protein expression oscillates in an HC-dependent manner. In telogen HFs, MPZL3 is localized to the secondary hair germ, an epicenter of HC regulation, partially co-localizing with P-cadherin, in contrast to the hair matrix localization during early-mid anagen. Intriguingly, keratin 14 promoter-driven Cre-mediated Mpzl3 knockout mice recapitulate the precocious telogen-anagen transition during the second HC observed in global Mpzl3 knockout mice, indicating that skin epithelia-derived, MPZL3-dependent signals dictate the HCC. These findings introduce the novel concepts that a) mitochondria are more actively involved in HC control than previously recognized in the context of energy metabolism, b) MPZL3 plays a central role in the elusive HCC, and c) targeting MPZL3 and/or its downstream effectors may constitute an innovative and effective strategy for therapeutic HC manipulation in alopecia treatment.