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

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.