Exploring mitochondrial dysfunction in miniaturized hair follicles: Insights into androgenetic alopecia

Summary: Abstract Body: Androgenetic alopecia (AGA) is the most common type of alopecia. The pathological hallmark of AGA is miniaturization, where terminal hairs transform into vellus hairs and eventually disappear. AGA exhibits a distinct patterned distribution, with follicles in androgen- sensitive areas like vertex undergoing miniaturization, while occipital follicles remain unaffected. The metabolic processes of hair follicles, particularly mitochondrial metabolism, remain poorly understood. Current studies suggest that hair follicle respiration primarily relies on aerobic glycolysis. In AGA, only one study showed that dermal papilla cells(DPC) in balding areas exhibit mitochondrial dysfunction to non-balding areas, yet mechanistic insights remain limited. To explore these changes, we analyzed miniaturized follicles from the vertex and normal follicles from the occipital region，both in anagen, of AGA patients using bulk RNA sequencing and single-cell transcriptomics. Data revealed elevated mitochondrial activity in miniaturized follicles, especially in DPCs, including transcriptional upregulation of mitochondrial synthesis, degradation, mitophagy, and ROS production. IF staining demonstrated the characteristic expression of mitophagy-related proteins in DPCs of miniaturized follicles. Structural analysis using TEM showed mitochondrial abnormalities, including disrupted membrane structures, endoplasmic reticulum stress, and mitophagy in DP cells in vertex . Functional assays using mitochondrial probes revealed decreased membrane potential, elevated ROS production etc. in vertex follicles. IF staining of related proteins confirmed these results. Furthermore, we also obeserved impaired aerobic glycolysis in miniaturized follicles. This study is the first to combine high-throughput transcriptomics with mitochondrial staining to identify distinct mitochondrial phenotypes in miniaturized follicles. Based on observations, we hypothesize that reduced aerobic glycolysis leads to compensatory mitochondrial respiration, which results in structural and functional mitochondrial damage in AGA. Yuou Sha¹, Qingmei Liu¹, Jinran Lin¹, Wenyu Wu¹ 1. Huashan Hospital Fudan University, Shanghai, Shanghai, China. Translational Studies: Cell and Molecular Biology