The HEAT Repeat Protein MROH1 Deficiency Leads to Reduced Circulating Thyroid Hormone Levels in Mice.

Abstract

Introduction: Systemic metabolism critically depends on thyroid hormones, whose release relies heavily on proper lysosomal function for thyroglobulin degradation. MROH1, a highly conserved mediator of lysosomal membrane fission, is predominantly expressed in the human thyroid gland; however, its physiological role within endocrine systems remains unexplored. This study investigated the impact of MROH1 deficiency on thyroid function using a novel global Mroh1 knockout (KO) mouse model.

Methods: Metabolic phenotypes, including body weight and serum biochemical parameters (FT3, FT4, TSH, and cholesterol), were evaluated in male Mroh1-KO mice and their controls. Thyroid architecture and gene expression profiles were investigated via histological analysis and quantitative reverse transcription-PCR (qRT-PCR). Lysosomal function was assessed using immunoblotting and cathepsin L proteolytic activity assays in primary thyroid cells and whole-tissue lysates.

Results: Mroh1-KO mice showed reduced circulating thyroid hormone levels characterized by significantly reduced serum FT4 and FT3 levels, a gradual increase in body weight, and hypercholesterolemia. Histological analysis of aged Mroh1-KO mice revealed an altered thyroid architecture, featuring smaller follicle sizes and the replacement of follicles with adipocyte-like structures. Although lysosomal biogenesis and cathepsin L protease activities remained preserved, the expression of key thyroid differentiation regulators (Nkx2-1, Foxe1) and their downstream targets (Tg, Mct8) were significantly downregulated.

Conclusions: Global Mroh1 deficiency is associated with reduced circulating thyroid hormone levels, thyroid architectural remodelling, and downregulated thyroid-specific gene expression. These findings demonstrate that MROH1 is important for maintaining thyroid gland hormone homeostasis and structural integrity.