Progress on mitochondria and hair follicle development in androgenetic alopecia: relationships and therapeutic perspectives

Abstract

Hair loss has long been a significant concern for many individuals. Recent studies have indicated that mitochondria play a more crucial role in hair loss than previously recognized. This review summarizes the connection between mitochondrial dysfunction and hair follicle development, outlines the links between diseases related to mitochondrial disorders and hair issues, and highlights the influence of mitochondrial dysfunction on androgenetic alopecia. We discuss the cellular and signaling mechanisms associated with hair loss and examine how mitochondrial dysfunction, such as insufficient energy supply, signaling irregularities, protein/gene abnormalities, and programmed cell death, can hinder the normal proliferation, differentiation, and growth of hair follicle cells. Furthermore, we discuss current treatment approaches and potential innovative therapies, including mitochondrion-targeting drugs and advanced techniques that directly target hair follicle cells, providing fresh insights into the crucial role of mitochondria in maintaining hair follicle health and managing hair disorders. Furthermore, this review explores future therapeutic strategies and proposes that mitochondrial research could lead to groundbreaking treatments for hair loss, thus providing optimism and new avenues for the treatment of individuals experiencing hair loss. This review not only underscores the central importance of mitochondria in hair health but also emphasizes the importance of advancing research and treatment in this field.

Graphical abstract

Introduction

Hair loss is a widespread issue affecting up to 80% of men and 40% of women globally [1]. It seriously affects an individual's self-esteem and social interactions [2], with androgenetic alopecia (AGA) being the most common type of hair loss [1]. Hair loss usually results from dysfunction of hair follicles, which is influenced by androgen levels and follicular sensitivity to these hormones, causing follicle shrinkage and shortened hair life cycles. In addition, mitochondrial dysfunction plays an important role in hair loss [3]. Mitochondria are responsible not only for energy production but also for various cellular activities, including cell death and differentiation [4]. Previous studies have associated mitochondrial diseases with skin disorders and hair abnormalities, with rashes and hair issues being common symptoms [5]. A French study categorized skin manifestations in pediatric patients with mitochondrial diseases into four main groups: hair abnormalities, rash and pigmentation disorders, hirsutism, and violet extremities [6]. Research has indicated that in patients with AGA, dihydrotestosterone (DHT) not only directly impacts hair follicles but also exacerbates hair follicle cell dysfunction by inducing oxidative stress in mitochondria [7]. This discovery offers a fresh perspective on understanding AGA and suggests that addressing this condition may involve focusing on maintaining mitochondrial health.

Hair follicles

Hair follicles are essential structures in skin development, and they undergo cycles of renewal comprising the anagen, catagen, and telogen phases [8]. The anagen phase determines the length of the hair shaft, primarily through the action of the inner root sheath (IRS) and the hair shaft. The catagen phase is characterized by a significant reduction in the cell cycle due to increased apoptosis in hair follicle cells. This phase concludes when the hair bulb assumes a club-like shape, indicating the termination of active hair growth. The catagen phase subsequently transitions into the telogen phase, a period of rest during which the follicle remains inactive until it is reactivated to initiate a new anagen phase [9]. Various hair loss disorders of clinical significance stem from the early termination of the active anagen phase [10]. Various factors, both internal and external, can impact hair follicle development, including mitochondrial dysfunction [11]. Key signaling pathways, such as the Wnt/β-catenin and bone morphogenetic protein (BMP) pathways, regulate the hair cycle, with Wnt/β-catenin activation promoting growth by supporting stromal cell proliferation, whereas TGF-β/BMP activation inhibits growth by triggering apoptosis in the catagen phase [12].

The hair follicle is anatomically divided into three parts: the funnel, the isthmus, and the bulb. The cells at the base of the follicle produce new hairs via division and differentiation, whereas the dermal papilla (DP) of the bulb promotes hair growth. Structurally, the hair follicle consists of an IRS and an outer root sheath (ORS). The ORS connects epidermal basal cells and serves as a reservoir for hair follicle stem cells (HFSCs). The activation of HFSCs is controlled by signaling molecules released from the DP located underneath the bulge. Factors released from the DP regulate the state of stem cells, and when a critical concentration is reached, HFSCs begin to enter the anagen phase [13].

HFSCs

Hair cycle regulation is governed primarily by HFSCs, which have high potential for differentiation [14]. HFSCs play a key role in hair follicle regeneration, skin healing, maintenance of hair follicle structure and cyclic activity, response to external stimuli, and promotion of wound healing [15]. This process involves multiple signaling pathways, including the Wnt/β-catenin, Hedgehog (Hh), Notch, BMP, and apoptotic signaling pathways [16].

Wnt signaling is essential for the differentiation and proliferation of HFSCs and influences the hair follicle cycle [17]. Hh signaling enhances the activation pathway for HFSC development, although its precise role requires clarification [2]. Regulatory T cells (Tregs) can promote the proliferation and differentiation of HFSCs by expressing the Notch ligand Jagged-1 (Jag1), thereby facilitating hair follicle regeneration [18]. BMP signaling is critical for maintaining the quiescent state of HFSCs during self-renewal and preserving the cellular properties necessary for the generation of transiently expanded cells (TECs). Attenuation or inhibition of BMP signaling activates HFSCs, as observed in the abnormal activation of quiescent HFSCs in mice lacking Bmpr1a expression [2].

Dermal papilla cells

Dermal papilla cells (DPCs) play a key role in regulating hair growth and development by influencing HFSCs through secreted factors that initiate the anagen phase of hair follicles [19]. However, as DPCs age, they hinder the renewal and differentiation of HFSCs, ultimately leading to hair loss [20]. The activation of Wnt signaling is vital for promoting hair growth [21], whereas the activation of ERK in the phosphoinositide 3-kinase/AKT (PI3K/AKT) and MAPK pathways stimulates DPC proliferation [22]. The versican (VCAN) gene has been identified as a key player in hair follicle development, with increased expression of VCAN correlated with improved hair follicle formation [22,23,24].

HFSCs and DPCs are vital in hair follicles and ensure optimal conditions for hair regeneration and growth [21]. The aforementioned signaling pathways are discussed in more detail in the following sections.

Hair follicle keratinocytes

The keratinocytes of the ORS are responsible for producing essential growth factors that control the hair follicle cycle [25]. Specifically, insulin-like growth factor 1 (IGF1) expression increases anagen, whereas TGFβ1 and TGFβ2 expression initiates catagen. ORS keratinocytes not only are equipped with highly functional mitochondria and other skin cells but also have the capacity to produce different keratin proteins [19].

Overall, ORS keratinocytes represent a cell population with significant potential and may serve as a secondary major regulatory center of hair follicle activity in addition to the DP.

Other cells

Matrix cells in the hair bulb exhibit a high mitotic rate and act as the primary proliferative cells during the anagen phase. Melanocytes, located in the inner layers of these cells within the matrix region of the hair follicle, are responsible for melanin production, determining its color [17, 19]. Fibroblasts (including specialized types such as DPCs) provide support and nourishment to the connective tissue sheath near hair follicles, whereas immune cells such as macrophages and Langerhans cells participate in immune surveillance. The adipocytes surrounding hair follicles play a significant role in their growth cycle [19]. The vascular cells surrounding hair follicles supply essential nutrients and oxygen for healthy development.

Signaling pathways/molecules involved in hair follicle development

Wnt/β-catenin signaling

Wnt/β-catenin signaling is essential for hair follicle growth and influences cell differentiation and the hair cycle, particularly during the transition between the anagen and telogen phases [14, 26]. Wnt signaling promotes the accumulation of β-catenin, which translocates to the nucleus to regulate gene transcription and drive hair follicle cell differentiation. The level of β-catenin affects HFSC differentiation and overall follicle development [27]. Abnormal β-catenin expression can lead to structural hair follicle issues or hair loss [28]. WNT10b, a key activator of this pathway, is crucial for the transition of hair follicles into the anagen phase [29, 30], whereas inhibitors such as DKK1 and sFRP1 regulate this process to prevent excessive HFSC proliferation [2].

BMP signaling

BMP signaling, which is initiated through the phosphorylation of BMP and subsequent receptor interactions, plays a crucial role in the regulation of HFSC proliferation and differentiation through the involvement of Smad proteins [2]. Smad proteins, particularly Smad4, play a central role in transmitting TGF-β signals from the cytoplasm to the nucleus, which is essential for hair follicle development and differentiation [31, 32]. BMP-2 and BMP-4 are key to hair follicle development: BMP-2 promotes hair shaft formation, whereas BMP-4 affects follicle growth and HFSC differentiation [33]. BMP-2 expression increases during the telogen phase, whereas BMP-4 expression peaks during catagen, indicating its role in hair cycle regulation [34]. BMP and Wnt signaling cooperate in maintaining HFSCs, with DKK3 inhibiting Wnt signaling in a feedback loop with BMP-4 [14, 35,36,37]. Additionally, miR-29a/b1 modulates BMP signaling by downregulating Bmpr1a, influencing the hair growth cycle [38].

Notch signaling

Notch signaling is integral to the regulation of hair follicle formation and re-epithelialization. Its evolutionary conservation is particularly significant during the advanced stages of embryonic hair follicle development [39, 40]. In mammals, Notch signaling involves four receptors (Notch 1–4) and five ligands (Delta-like 1 [Dll-1, 3, 4], Jagged-1, and Jagged-2), which interact through cell‒cell binding [41]. Upon binding, the Notch receptor undergoes cleavage by γ-secretase, resulting in the release of the Notch intracellular domain (NICD). The NICD subsequently translocates to the nucleus, where it binds to DNA, initiates gene transcription, and activates downstream responses of Wnt/β-catenin signaling, leading to various biological effects [42].

Hh signaling

Hh signaling begins when Shh binds to its receptor Patched (PTCH), activating Smoothened (Smo) and allowing Gli proteins to enter the nucleus, triggering target gene transcription [43, 44]. This pathway supports hair follicle formation, repair, and stem cell maintenance [14]. Hh signaling stimulates dormant HFSC proliferation and plays a role in the regeneration of hair follicles [45]. However, abnormal activation, such as reduced PTCH expression in basal cell carcinoma, can disrupt normal hair growth [46]. Additionally, Hh signaling interacts with Wnt/β-catenin to promote hair follicle maturation during embryonic development [47].

PI3K/AKT signaling

PI3K/AKT signaling is crucial for hair follicle growth, particularly during the transition from the telogen phase to the anagen phase. AKT, a pivotal component in cell survival, inhibits pro-apoptotic proteins, thereby protecting cells from apoptosis [48]. Furthermore, the signaling pathway also promotes the proliferation of HFSCs and interfollicular epidermal stem cells [49,50,51]. Additionally, it contributes to hair follicle regeneration and wound healing processes by initiating the release of cytokines and growth factors [52]. Moreover, the interaction between long noncoding RNA and miR-21 has been shown to enhance the activation of PI3K/AKT signaling [53].

RAS/MAPK signaling

RAS/MAPK signaling involves key kinases (ERK, JNK, p38) that transmit signals from the cell surface to the nucleus, influencing gene expression through phosphorylation [12]. This pathway regulates the hair cycle and HFSC self-renewal, with GAB1 playing a crucial role in controlling these processes [12, 54]. Additionally, RAS/MAPK activation can affect other pathways, such as the inhibition of Shh expression, highlighting its complex role in hair follicle dynamics and maintenance [54]. (Fig. 1 depicts the signaling pathways that play crucial roles in the growth and development of hair follicles.)

Fig. 1

Key signaling pathways involved in various cell types within the hair follicle

Wnt/β-catenin signaling is recognized for its crucial role in regulating HFSCs, DPCs, and keratinocytes. Additionally, the Hh, Notch, and BMP signaling pathways also contribute to the control of HFSCs. Moreover, the PI3K/AKT and RAS/MAPK signaling pathways are predominantly active in DPCs. This depiction highlights the complex interactions and connections between various signaling pathways that impact the destinies and functions of hair follicle cells.

Mitochondrial structure and function

Mitochondria are essential for regulating intracellular and extracellular signaling pathways, acting as central hubs in these processes. They significantly impact cell survival, fate, differentiation, and growth.

Mitochondrial structure

Mitochondria consist of two distinct membranes: an outer membrane that selectively filters small molecules and an inner membrane characterized by invaginations known as cristae, which increase the surface area to facilitate various biochemical reactions [55]. The inner membrane exhibits selective permeability, allowing the passage of molecules such as oxygen, carbon dioxide, and water. Furthermore, it plays a critical role in the transport of proteins involved in the transfer of adenosine triphosphate (ATP) and pyruvate between the cytoplasm and the mitochondria [56]. The region enclosed by the inner membrane, known as the mitochondrial matrix, contains enzymes and mitochondrial DNA (mtDNA), both of which are essential for energy production and the overall functionality of the cell. These specialized structural features enable mitochondria to regulate critical biological processes, including ATP synthesis, calcium homeostasis, and apoptosis [57,58,59].

Mitochondrial function

ATP synthesis

ATP, recognized as the primary unit of cellular energy, is synthesized through oxidative phosphorylation, which occurs in the inner membrane of the mitochondria—organelles responsible for energy production. This process involves specialized protein complexes that facilitate the conversion of nutrients, including glucose and fatty acids, into bioavailable energy [56]. Mutations in mitochondrial DNA (mtDNA) and the intrinsic aging process can compromise cellular energy metabolism by disrupting mitochondrial function, which in turn reduces ATP production [55].

Mitochondrial ROS and oxidative stress

Reactive oxygen species (ROS) are produced as byproducts of mitochondrial respiration and serve dual functions in both cellular signaling and potential damage [3, 60]. Cells maintain a critical balance between the production and removal of ROS to ensure their health. When this balance is disrupted, the accumulation of ROS can exceed the capacity of cellular antioxidant defenses, resulting in oxidative stress and subsequent cellular dysfunction [3, 61,62,63]. In metabolically active cells, abnormalities in mitochondrial proteins can lead to increased oxidative stress and disrupt cellular function, which can significantly impact hair growth [8, 64].

Mitochondrial apoptosis

Mitochondria not only serve as energy-producing organelles of the cell but play crucial roles in regulating the cellular life cycle. During programmed cell death, mitochondria release specific signaling molecules such as cytochrome c, which subsequently activate certain proteases known as caspases to initiate cell death [65,66,67,68]. Additionally, mitochondrion-specific proteins, such as apoptosis-inducing factor (AIF), can promote cell death through pathways that do not depend on caspase activation [69].

Mitochondrial fusion, division, and mitophagy

Mitochondria sustain their function through continuous processes of fusion and fission, working like a dynamic repair system. Fusion enables damaged mitochondria to merge with healthy mitochondria to improve energy production efficiency. This process is regulated by proteins such as MFN1 and OPA1 [70, 71]. Fission, regulated by DRP1, facilitates the even distribution of mitochondria and enables the identification of damaged regions for removal. Under the influence of PINK1 and PARKIN, damaged mitochondria subsequently undergo degradation through a process known as mitophagy, which is crucial for maintaining cellular health [72, 73].

Mitochondria and hair follicles

Mitochondria are critical to the growth and function of hair follicles [74]. Keratinocytes in the human epidermis and hair follicles contain the highest concentrations of mitochondria [74]. Studies have established a strong connection between mitochondrial dysfunction and hair disorders [5]. Additionally, mitochondria are responsible for regulating signaling pathways in the hair follicle cycle. Expanding on the specific signaling mechanisms of hair follicle development mentioned earlier, the following section offers a comprehensive explanation of how mitochondria impact these signaling pathways in hair follicle development.

Signaling pathways and mitochondria in hair follicles

Mitochondrial regulation of Wnt-β-catenin signaling

Mitochondria are crucial regulators of signaling pathways that drive hair follicle development, with mitochondrial ROS playing a key role in the Wnt-β-catenin signaling pathway. In mitochondrial transcription factor A (TFAM)-deficient mice, keratinocytes fail to generate mitochondrial ROS, which disrupts the transmission of the Wnt-β-catenin signals essential for hair follicle development [75]. The absence of mitochondrial ROS leads to impaired Wnt signaling, reducing β-catenin levels and resulting in premature catagen, a phase characterized by hair follicle regression [3].

Mitochondrial regulation of Notch signaling

Mitochondria are integral to the regulation of the Notch signaling pathway, which plays a crucial role in keratinocyte differentiation and hair follicle development. Studies in Drosophila follicle cells have shown that the downregulation of Dynamin-related protein-1 (DRP1), a protein involved in mitochondrial fission, leads to hyperfused mitochondria and inactivates Notch signaling [76]. This, in turn, inhibits follicle cell differentiation but maintains cell proliferation. The mechanism by which mitochondrial shape affects Notch signaling remains unclear, although recent evidence suggests that mitochondrial morphology may influence Notch activity during cellular differentiation processes [3].

In TFAM-deficient mouse models, the absence of mitochondrial ROS disrupts the transduction of Notch signals, impairing both epidermal and hair follicle differentiation [75]. Specifically, TFAM-deficient keratinocytes exhibit reduced expression of Notch target genes, including Hes1, Hey1, and Hey2, which are essential for keratinocyte differentiation. The lack of mitochondrial ROS generation also prevents the activation of key transcripts involved in epidermal structure, such as KRT1 and KRT10, further supporting the role of Notch signaling in hair follicle homeostasis [77].

Mitochondrial regulation of MAPK-ERK-Mfn2 signaling

Sirtuin 1 (SIRT1), an NAD-dependent deacetylase, plays a key role in maintaining mitochondrial homeostasis and protecting HFSCs from inflammation-induced damage [78].

The protective effects of Sirt1 in HFSCs are mediated through the MAPK-ERK-Mfn2 signaling axis. Activation of this pathway is crucial for preserving mitochondrial function, as inhibition of the MAPK-ERK-Mfn2 pathway negates the ability of Sirt1 to promote HFSC survival, mobility, and proliferation under inflammatory conditions. In TNFα-treated HFSCs, Sirt1 overexpression restored mitochondrial respiratory complex expression and improved glucose uptake and lactic acid production, further supporting mitochondrial metabolism. This pathway highlights the critical role of mitochondrial dynamics in stem cell maintenance, especially in the context of inflammatory stress [75, 78].

Mitochondrial regulation of TGF-β/Smad signaling

Studies have shown that key molecules involved in the apoptotic process, such as the anti-apoptotic protein Bcl-2 and the pro-apoptotic proteins Bax, TGF-β2, and cleaved caspase 3, play crucial roles in hair loss. Inhibition of TGF-β2 enhances the expression of Bcl-2 while reducing the expression of Bax and cleaved caspase 3. This modulation, in turn, helps maintain a balance between pro- and anti-apoptotic signals, reducing excessive cell death and preserving hair follicle function [79].

Mitochondrial regulation of PI3K/AKT signaling

Studies have shown that the activation of the PI3K/AKT pathway enhances mitochondrial activity and promotes cell survival. One of the key outcomes of PI3K/AKT activation is the stimulation of cAMP response element-binding protein (CREB), which directly binds to mitochondrial DNA and facilitates the expression of mitochondrial genes involved in cell survival (such as Bcl-2) and mitochondrial biogenesis (such as PGC-1α) [75]. (For the mitochondrial regulation of hair follicle signaling pathways, see Fig. 2 and Table 1.)

Fig. 2

Hair follicle signaling pathways associated with mitochondria

Table 1 Hair follicle signaling pathways associated with mitochondria

Effects of mitochondrial damage on hair follicle health

Differentiation and barrier maintenance of keratinocytes

Mitochondria play pivotal roles in cellular energy production, ROS generation, and apoptosis, all of which are critical for hair follicle development and maintenance [60]. Studies have demonstrated that mitochondrial dysfunction, particularly in the electron transport chain, can impair hair follicle health by disrupting the delicate balance of cellular metabolism and the stress response [77, 80].

Mitochondrial dysfunction primarily impacts hair follicle cells, such as keratinocytes and DPSCs, by altering their energy metabolism. In particular, keratinocytes require mitochondrial ATP production for their proliferation and differentiation. Impaired mitochondrial function results in decreased ATP levels and increased ROS, which can cause oxidative damage to cellular components, ultimately triggering premature follicle aging or entry into the catagen phase. Moreover, excessive ROS can activate apoptotic pathways, further exacerbating hair follicle cell death and contributing to hair loss [60, 81].

In mouse models with disrupted mitochondrial function, such as those deficient in mitochondrial TFAM, researchers observed significant defects in hair follicle development [77]. These defects are often associated with reduced mitochondrial ROS generation, which is critical for activating signaling pathways, such as the Wnt-β-catenin pathway, which is essential for follicle development and maintenance [82,83,84]. In the absence of functional mitochondria, key signaling molecules fail to activate, resulting in impaired follicle growth and increased susceptibility to external stressors [85].

In addition to ROS, calcium signaling between mitochondria and the endoplasmic reticulum (ER) is vital for maintaining cellular homeostasis [86]. Disruption of mitochondrial calcium uptake can hinder ATP production and activate the mitochondrial permeability transition pore, promoting cell death and further compromising hair follicle health [60].

Hair follicle morphogenesis

CRIF1, a nuclear protein that regulates transcription factors, also plays a crucial role in mitochondrial protein synthesis and the integration of oxidative phosphorylation polypeptides into the mitochondrial membrane [87]. Previous studies have shown that mouse embryonic fibroblasts lacking CRIF1 expression exhibit notable mitochondrial dysfunction, which impacts the transcriptional activation of β-catenin. This dysfunction has been linked to abnormalities in skin differentiation and hair morphology, ultimately delaying the hair growth cycle [88, 89].

AIF is a mitochondrial protein crucial for both energy production and the regulation of apoptosis. In hair follicles, AIF.

facilitates the transition from the anagen phase to the catagen phase by initiating apoptosis upon its release from the mitochondria. Mitochondrial dysfunction, which impairs normal AIF activity, can result in irregular hair follicle cycles, ultimately contributing to hair loss or abnormal growth [90].

In mitochondrial disorders such as Friedreich ataxia (FRDA), frataxin deficiency leads to oxidative stress and compromised hair follicle structure, resulting in thin, weak hair shafts and cuticular damage [91]. ROS generated by dysfunctional mitochondria disrupt keratinocyte differentiation and the hair growth cycle, contributing to hair loss. These findings suggest that mitochondrial dysfunction directly causes oxidative damage, leading to structural abnormalities in hair follicles and subsequent hair loss [92, 93].

Krtap11-1 is a protein located in mitochondria that plays a key role in hair follicle development by regulating signaling pathways such as the Wnt and BMP pathways. Its expression varies during different phases of anagen, peaking during the catagen and telogen phases. Mitochondrial dysfunction can impair the normal function of Krtap11-1, leading to issues in keratinocyte differentiation and oxidative stress regulation. This can result in weak hair shafts and hair loss, highlighting the importance of proper mitochondrial function for hair follicle health [64].

The MPZL3 protein is a mitochondrially localized, nuclear-encoded protein that plays a pivotal role in regulating key physiological processes, including ROS production, lipid metabolism, and energy balance [94]. Disruption of MPZL3 function, as observed in MPZL3 global knockout (GKO) mice, results in premature entry into the anagen phase and various skin abnormalities. The ability of MPZL3 to regulate mitochondrial activity is essential for maintaining the balance between cellular differentiation and homeostasis, particularly in the sebaceous glands of hair follicles. Dysfunctional MPZL3 impairs mitochondrial dynamics, disrupts hair follicle cycling and contributes to conditions such as seborrheic dermatitis-like skin inflammation [8].

Cutaneous energy metabolism and its stressors

HFs operate through an internal metabolic cycle akin to the Cori cycle, which plays a key role in hair growth and development. This study revealed that human hair follicles store glycogen, particularly in the ORS, and that this glycogen is metabolized to generate energy essential for the maintenance of hair follicles. The presence and breakdown of glycogen in the ORS is critical during the hair cycle, with changes observed during different stages, such as anagen and catagen. Mitochondrial dysfunction affecting glycogen metabolism could disrupt energy production, thereby impacting hair growth and leading to abnormalities such as premature onset of catagen [95].

Mitochondria support both anaerobic and aerobic respiration. HFSCs predominantly rely on anaerobic mitochondrial metabolism [96], whereas differentiated cells favour aerobic metabolism. Aerobic respiration in mitochondria is essential for the differentiation and functionality of HFSCs. As HFSCs undergo differentiation, there is a transition in mitochondrial activity from glycolysis to oxidative phosphorylation to meet the increased energy demands. Mitochondrial dysfunction, particularly impaired oxidative phosphorylation, can delay hair regeneration and negatively impact hair follicle health [97,98,99,100]. In addition to respiration, mitochondria significantly contribute to other energy processes, thereby enhancing the energy supply derived from glycolysis, which serves as the primary energy source for hair follicles [96].

Inhibiting the entry of pyruvate into mitochondria disrupts normal oxidative metabolism and accelerates the hair growth cycle, stimulating hair follicle regrowth even in conditions of alopecia [101, 102]. Furthermore, enzymes involved in fatty acid synthesis and elongation, such as stearoyl-CoA desaturase (SCD), are crucial for lipid production in sebaceous glands and skin, which support hair follicle hydration and maintain barrier integrity. Deficiencies in fatty acid metabolism can impair the hair growth cycle, lead to structural damage, and reduce the viability of hair follicles [103, 104].

Novel neuroendocrine regulation in hair follicles

Research interest in the impact of neurohormonal signaling on skin physiology has grown, particularly regarding how hair follicles function as endocrine organs influenced by the hypothalamus‒pituitary‒thyroid (HPT) axis [11]. Thyroid hormones play a vital role in regulating hair follicle physiology by prolonging the anagen phase, promoting keratinocyte proliferation, and affecting pigmentation [10, 105]. Notably, mitochondria not only serve as cellular "powerhouses" but also perform endocrine functions, providing cells with the necessary energy and signals for their function [106]. Thyroid hormones enhance mitochondrial function, improving hair follicle growth, thermogenesis, keratinocyte proliferation, and keratin expression [82, 107, 108]. Previous research has demonstrated increased expression of mitochondria-encoded cytochrome c oxidase subunit 1 (MTCO1) in human scalp hair follicles cultured under the influence of the HPT axis [109]. Thyroid hormones and associated neuroendocrine signals stimulate mitochondrial biogenesis and activity, particularly in the ORS of hair follicles. Mitochondrial dysfunction, resulting from imbalances in hormonal control, can impair ATP production, leading to reduced energy availability for hair follicle maintenance and growth. This disruption may negatively affect the hair growth cycle, potentially contributing to hair loss due to insufficient mitochondrial energy output [108]. (The effects of mitochondrial damage on hair follicle health are illustrated in Fig. 3.)

Fig. 3

Impact of mitochondrial abnormalities on hair follicle development

Involvement of mitochondrial dysfunction in hair-related disorders

Mitochondrial dysfunction is recognized as a significant contributor to various hair diseases. In conditions such as lichen planopilaris, notable mitochondrial abnormalities have been observed in external hair follicle stem cells (EHFSCs) [110, 111]. These abnormalities are consistent with skin-related manifestations, including hair and pigmentation issues, rashes, and acrocyanosis, which occur in approximately 10% of individuals with primary mitochondrial diseases [74].

Mitochondrial homeostasis is intricately regulated by Sirtuin 1 (SIRT1), a histone deacetylase that is primarily activated by the MAPK/ERK/Mfn2 pathway. Reduced expression of SIRT1 results in mitochondrial dysfunction, which triggers an inflammatory stress response mediated by TNF-α in HFSCs. This dysfunctional cascade is particularly pronounced in conditions such as AGA, where DHT induces mitochondrial dysfunction, ultimately leading to aging of the DPCs in AGA [112].

Research has revealed that children with mitochondrial diseases frequently display symptoms such as slow hair growth and fragile, thinning hair [6]. This is likely due to mitochondrial dysfunction, which impairs oxidative phosphorylation and results in a decreased energy supply to hair follicle cells. This disruption affects normal hair follicle cycling and regeneration. One study reported that individuals with progressive mitochondrial encephalopathy exhibit fragile hair characterized by longitudinal grooves and a loss of keratinocytes [113]. Additionally, research on FRDA has underscored its effects on hair health, as both carriers and patients frequently present with fragile hair follicles [91]. These findings emphasize the significant role of mitochondrial dysfunction in various hair disorders.

Mitochondrial oxidative phosphorylation is crucial for ATP generation and the regulation of ROS levels to support the differentiation of keratinocytes. Both aerobic and anaerobic respiration within mitochondria contribute to the proliferation and activity of hair follicle cells. Mitochondrial TFAM influences the transcription of the β-catenin signaling pathway, whereas the mitochondrial ribosomal protein CRIF1 impacts both β-catenin signaling and the hair follicle growth cycle. AIF, located in the mitochondrial inner membrane, triggers caspase-independent apoptosis in follicle cells. The hydrophilic protein Krtap11-1 in mitochondria significantly influences the WNT and BMP signaling pathways. The myelin protein zero-like 3 (MPZL3), a nuclear-encoded mitochondrial protein, also affects the hair growth cycle. Additionally, mitochondrial-encoded cytochrome c oxidase subunit 1 (MTCO1) expression is upregulated by the HPT axis within hair follicles, thereby promoting their growth and development.

Treatment progress

Multiple studies have demonstrated the effectiveness of specific medications in managing hair loss associated with mitochondrial dysfunction, which has sparked a variety of new research objectives in this field.

Hair follicle-targeted therapies

DHT plays a role in accelerating the aging process in DPCs by inducing mitochondrial dysfunction, leading to hair loss [114, 115]. Therapies such as stem cell treatment and hair bioengineering, particularly the use of micrografts containing autologous hair follicle mesenchymal stem cells (HF-MSCs), provide safe and effective methods for improving hair count and density in AGA patients [21]. Platelet-rich plasma (PRP) therapy, which harnesses the growth factors present in platelets, has been shown to stimulate HFSCs, promote new hair follicles and significantly improve hair count, density, and scalp thickness in individuals with AGA [2].

Various drugs target specific signaling pathways in hair follicles to promote hair growth. For example, LSESR activates TGF-β/Smad signaling and reduces DHT-induced inflammation in areas of hair loss [79]. Quercitrin (quercetin-3-O-rhamnoside) activates MAPK/CREB signaling, enhancing cellular energy metabolism and growth factor secretion [75]. The monoterpenoid loliolide stimulates hair growth by activating the AKT and Wnt/β-catenin signaling pathways in DPCs [22]. The active compound of the rice capsule (ACPI) increases Wnt/β-catenin signaling, promoting hair growth and prolonging the anagen phase of the hair cycle. Cosmetic formulations such as ShPI and HtPI containing ACPI can prevent hair aging, reduce COL17A1 degradation in hair follicles exposed to ultraviolet radiation, and regulate androgen metabolism by decreasing DHT production [28]. Additionally, lithium chloride has been found to ameliorate follicular defects related to β-catenin transcriptional issues, resulting in increased follicular length [77].

Mitochondrion–targeted therapies

Mitochondrial function is regulated by a variety of hormones and plays a crucial role in maintaining skin and cellular health, especially in treatment and stress situations. For example, thyroid hormones stimulate mitochondrial biogenesis [107], glucocorticoids increase mitochondrial function to support cell energy requirements during acute stress [116], and vitamin D3 derivatives impact tissue differentiation and the function of various tissues [117], including skin health, by controlling the calcium balance. However, caution is essential when these treatments are used because of their potential toxic effects on mitochondria [118].

Cyanidin-3-O-arabinoside (C3A) has been identified as a natural compound that mitigates the slowing of hair growth induced by DHT and enhances the proliferation of HFSCs by preventing the accumulation of mitochondrial calcium [115]. Minoxidil may address AGA by elevating intracellular calcium levels and increasing ATP synthase activity, thereby fostering hair growth and preventing follicular atrophy [119]. Fisetin activates the SIRT1-mitochondrial axis and enhances keratinocyte activity [120], promoting hair growth [121, 122]. Melatonin, known for its recognized antioxidant and DNA repair properties [61, 123], effectively addresses mitochondrial dysfunction, diminishes ROS production, and minimizes hair follicle damage by assisting in the deacetylation of P53 proteins through SIRT1 to counteract DNA damage [124, 125].

Recent advances in low-intensity laser therapy have shown promising results in promoting hair follicle development and regeneration. By utilizing the ability of mitochondria to absorb photons to increase ATP production and nitric oxide release, this therapy improves blood circulation and increases ROS levels, creating an optimal environment for hair growth [126]. Specific laser settings effectively stimulate DPC proliferation and upregulate the expression of important hair development genes, such as Sox2 and Fgf7 [127,128,129].

Moreover, novel drug delivery methods are attracting increasing interest. Microneedle technology has shown promising therapeutic effects and has been applied in the treatment of AGA [130]. A recent study introduced a microneedle patch integrated with cerium nanozymes (CeNZ), which reshaped the microenvironment around hair follicles by reducing oxidative stress and promoting angiogenesis. This innovative delivery method not only enables precise delivery of CeNZs but also stimulates vascularization around hair follicles, supporting hair regrowth more effectively than traditional treatments such as minoxidil [131,132,133,134].

PPARγ signaling is essential for regulating human hair follicle growth. MHY553, a PPARγ agonist [135], has garnered increased attention in dermatological research because of its ability to activate PPARγ in the skin, leading to the elimination of ROS and decreased expression of inflammatory cytokines [121].

ROS scavengers have been shown to be effective in treating skin conditions associated with high ROS levels [136]. Several clinical trials have investigated the use of antioxidants for the treatment of skin diseases [74]. Targeted antioxidants, such as mitoquinone (MitoQ), demonstrate promising therapeutic effects by efficiently entering mitochondria, which is enhanced by the inherent accumulation of iron in mitochondria [136].

Stem cell regeneration therapy has potential for treating conditions such as hair loss, and adipose-derived stem cell (ADSC) therapy has been shown to stimulate hair growth through the promotion of mitochondrial division [137]. However, elucidating the molecular pathways within the inflammatory microenvironment that can deplete stem cells to improve the efficacy of stem cell therapy is essential [78].(The advances in the treatment of alopecia are mediated by mitochondrial dysfunction are illustrated in Table 2.)

Table 2 Advances in the treatment of alopecia are mediated by mitochondrial dysfunction

Perspectives

Research on mitochondrial dysfunction in AGA is rapidly advancing, offering new therapeutic targets that focus on restoring mitochondrial health within hair follicles. These developments pave the way for innovative treatments aimed at enhancing mitochondrial function, which is critical for energy production and the survival of hair follicle cells. By focusing on mitochondrial-targeted therapies, researchers can explore new strategies for addressing AGA, shifting the focus from traditional approaches to targeting the underlying cellular dysfunction. These advancements offer promising prospects for more effective interventions in hair loss treatment. (Promising treatment strategies for AGA are illustrated in Fig. 4.)

Fig. 4

Promising treatment strategies for AGA

Potential therapeutic targets in hair follicles

Recent studies have revealed significant findings indicating potential new therapeutic targets in hair follicles. SCUBE3, a nontraditional TGF-β ligand, is essential for hair follicle growth, as it is secreted by DP fibroblasts and promotes hair growth. The expression pattern and function of SCUBE3 are partially conserved in human scalp hair follicles, suggesting that SCUBE3 expression could be a promising target for hair follicle therapy [74]. Additionally, Lepr has been identified as a characteristic gene of DP fibroblasts and is currently being investigated for targeted drug delivery in hair follicles. The LeprB-Cre genetic tool has been shown to be effective in targeting DP fibroblasts, indicating the potential for developing customized drug delivery systems for hair follicles on the basis of the specific expression of Lepr in these cells [138, 139]. Targeting DPC offers new strategies for treating hair loss. Activating Hh signaling promotes fibroblast states crucial for hair growth, including DP-like fibroblasts and adipocyte-fibroblast precursors, thus identifying a novel target for hair follicle therapies [138]. Biomarkers related to hair loss, identified through histologic techniques could serve as key targets for future treatments [140].

Targeting adipocytes for hair regeneration

Studies have shown that whole-layer craniomaxillofacial skin reconstruction using human-derived adipose stem cells and an extracellular matrix led to the development of hair follicle-like structures in regenerated tissues [141]. This discovery highlights the significant role that adipocytes play in hair follicle regeneration. The interaction between hair follicles and dermal white adipose tissue (dWAT) is crucial for the hair growth cycle [142, 143]. Further research has shown that dWAT secretes hepatocyte growth factor (HGF), which promotes hair follicle growth and pigmentation by activating the Wnt/β-catenin signaling pathway in hair matrix keratinocytes [144]. Additionally, dermal adipocytes are believed to shift from lipogenesis during the anagen phase to lipophagy and lipolysis during the catagen phase, thereby releasing free glycerol and cholesterol. This metabolic switch plays a regulatory role in the hair growth cycle [145]. Moreover, adipose stem cell extracts have demonstrated effectiveness in treating AGA [146], further emphasizing the importance of targeting adipocytes and their metabolic processes as a promising approach for AGA treatment.

Targeting mitochondrial receptors

Research has expanded to include mitochondrial targets for treating hair loss, as mitochondrial oxidative stress plays a significant role in conditions such as AGA. Key targets, such as SIRT1 and MPZL3, which are crucial for metabolism and stress responses, show promise in addressing hair follicle dysfunction [121, 135]. The Sirtuin family of proteins, particularly Sirtuins 1 and 3, has been recognized for their ability to reduce oxidative stress and influence keratinocyte differentiation. However, knowledge of specific activators of Sirt3 is lacking, and Sirt1 is the primary means of activation [147]. MPZL3, a protein localized to mitochondria, has been identified as an important regulator of the hair follicle cycle and plays a role in hair growth regulation as a downstream effect of PPARγ. PPARγ is a promising target for the treatment of mitochondrial dermatoses, and its use as a downstream effector of PPARγ could enhance the specificity of dermatological treatment and minimize adverse effects [74]. Recent research has suggested that cannabinoid receptor type 1 (CB1) inhibits mitochondrial function in keratinocyte-forming cells [148], with its activation in cell and mitochondrial membranes impacting hair growth [74]. This has led to speculation about the potential benefits of local therapeutic interventions through the selective activation of mtCB1 to reduce excessive mitochondrial ROS production resulting from dysregulated mitochondrial activity, thereby promoting hair growth.

Mitochondrial antioxidants

In addition, mitochondrial antioxidants such as MitoQ and SkQ1 offer potential solutions for the treatment of AGA. MitoQ, known for its antioxidant properties, has demonstrated therapeutic effects in neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease, whereas SkQ1, like MitoQ, is used in the cosmetic industry for its antiaging properties and ability to scavenge ROS and enhance cell viability. Mito-TEMPO and Mito-VitE are both powerful antioxidants with distinct mechanisms of action. Mito-TEMPO reduces ROS levels to prevent ROS-induced damage, while Mito-VitE effectively protects cells from oxidative stress and apoptosis [149]. A recent study demonstrated that N-acetylcysteine (NAC), which targets mitochondrial oxidative stress through its ROS-scavenging properties, effectively improved hair growth in men with early-onset AGA. The ability of NAC to reduce mitochondrial oxidative damage suggests its potential as a mitochondrial-targeted therapy for AGA when used alone or combined with minoxidil [150].

In addition to the role of antioxidants, recent advancements in mitochondrial drug delivery systems have markedly improved therapeutic efficacy. Conventional approaches, such as the use of triphenylphosphine (TPP), target mitochondria by interacting with the negatively charged mitochondrial membrane, thereby facilitating the delivery of lipophilic antioxidants such as MitoQ and Mito-TEMPO [149, 151,152,153,154]. Szeto-Schiller (SS) peptides, which accumulate on the inner mitochondrial membrane through electrostatic and hydrophobic interactions, exhibit lower toxicity and have demonstrated therapeutic benefits across various experimental models [151, 153]. Furthermore, nanocarrier-based systems, including MITO-Porter liposomes and self-assembled cationic carriers such as DQAsomes, broaden the potential for mitochondrial targeting by allowing precise antioxidant delivery [151,152,153,154,155,156]. Additionally, researchers have developed a fluorinated amphiphilic core–shell micelle system that enhances mitochondrial targeting by binding to mitochondrial phospholipids, particularly cardiolipin, and operates independently of membrane potential, thereby addressing the limitations associated with traditional cationic ligands [157].

In addition to the use of traditional antioxidants and drug delivery systems, emerging technologies such as microneedle-assisted delivery, have further broadened the possibilities for AGA treatment. Cerium oxide nanozymes have been integrated with microneedles, enabling antioxidants to be delivered approximately 300 microns deep into the skin for rapid drug release [131]. Recent research has improved the stability and targeting efficacy of CeNZ cerium nanoparticles by utilizing systems such as mesoporous silica carriers and graphdiyne-based nanocomposites [132, 133]. The integration of conventional antioxidants with advanced drug delivery systems, alongside novel methodologies such as microneedles, has established a robust framework for the development of mitochondrion-targeting therapies for AGA. Clinical studies have underscored the benefits of antioxidants in hair treatment. For example, a 24-week randomized, double-blind, placebo-controlled trial demonstrated that a topical regimen containing functional antioxidants significantly improved scalp condition, reduced hair shedding, and increased hair retention [158, 159]. However, while reducing oxidative stress is beneficial, it is essential to recognize that ROS also play a regulatory role in hair follicle cycling. Excessive suppression of ROS can disrupt these natural signaling pathways. Therefore, the therapeutic rationale for using antioxidants in AGA treatment should emphasize achieving a balance that mitigates oxidative damage without completely eliminating ROS, thus preserving the normal physiological processes of hair follicle growth.

Mitochondrial transfer

Recent research has demonstrated successful mitochondrial transfer in treating mitochondrial dysfunction-related diseases. In one study, researchers were able to transfer functional mitochondria from healthy donor cells to damaged cells, restoring their bioenergetic capacity and reducing oxidative stress [160]. Another study showed that mitochondrial transfer improved cell survival and recovery in models of ischemic injury, helping restore normal cellular metabolism [160].

Given that mitochondrial dysfunction is a critical factor in AGA progression, these findings suggest that mitochondrial transfer could be explored as a novel therapeutic approach for AGA. By replenishing damaged mitochondria in hair follicle cells, mitochondrial transfer may restore energy production, reduce oxidative damage, and support normal hair follicle cycling, offering a new direction for AGA treatment.

The pathogenesis of diffuse androgenetic alopecia, also known as female pattern hair loss, remains unclear [161]. However, studies have indicated an increase in apoptosis within the hair follicles of patients with FPHL [162]. In miniaturized hair follicles, there is elevated nuclear expression of the aryl hydrocarbon receptor [161], which regulates genes involved in mitochondrial biogenesis and function [163]. This regulation promotes keratinocyte apoptosis and contributes to follicle miniaturization. These findings suggest that targeting mitochondrial dysfunction may represent a promising therapeutic approach for FPHL, potentially reducing oxidative stress and mitigating hair follicle apoptosis. Further research is necessary to validate the effectiveness of mitochondrial-targeted therapies in female patients and to investigate their specific mechanisms of action. The focus on targeting mitochondria in AGA offers a promising new direction for treatment strategies. Directly addressing mitochondrial dysfunction within hair follicle cells can improve the cellular energy balance, reduce oxidative stress, and promote hair follicle health. As research advances, these mitochondrial-targeted approaches could revolutionize AGA treatment, marking the beginning of a new era in "mitochondrial dermatology" with potential applications for various skin conditions.

This figure illustrates potential therapies for AGA, focusing on mitochondrial-targeted treatments and the use of antioxidants to reduce oxidative stress. Additionally, mitochondrial transfer offers a novel method for restoring mitochondrial function. In hair follicle-targeted therapies, key targets include SCUBE3, Lepr, and the TGF-β signaling pathway, along with the supportive role of dermal adipose tissue in promoting hair growth.