Effects of Estrogen on the Mitochondrial Respiratory Chain

Estrogen is vital in regulating mitochondrial function, especially in the respiratory chain function. Studies have shown that estrogen directly affects mitochondrial metabolic activity through its receptors, such as ERα and ERβ. Estrogen promotes the assembly and activity of the mitochondrial respiratory chain complex, thereby increasing the energy production capacity of cells. For example, 17β-estradiol (E2) can enhance ATP synthesis within mitochondria and protect cells from oxidative stress by regulating mitochondrial membrane potential and reducing ROS production (Klinge 2020). In addition, estrogen also promotes mitochondrial biosynthesis and functional maintenance by regulating transcription factors associated with the mitochondrial respiratory chain, such as PGC-1α and NRF-1 (Tsialtas et al. 2021). These mechanisms suggest that estrogen is essential not only for mitochondrial function in physiological states but it may also exert a protective role in pathological states such as cardiovascular and neurodegenerative diseases.

Mechanisms by Which Estrogen Regulates Mitochondrial Biogenesis

Estrogen regulates mitochondrial biogenesis through a variety of mechanisms. First, estrogen activates PGC-1α, a critical transcriptional coactivator that promotes mitochondrial biosynthesis and function (Cho et al. 2022). Activation of PGC-1α promotes the transcription of mitochondrial DNA and enhances the expression of genes associated with energy metabolism, thereby increasing the number and function of mitochondria. In addition, estrogen regulates mitochondrial morphology and function by influencing mitochondrial dynamics, such as fusion and fission (Beikoghli Kalkhoran and Kararigas 2022). For example, estrogen can promote mitochondrial fusion, enhance the functional integrity of mitochondria, and reduce the risk of mitochondrial damage. It has also been found that estrogen enhances mitochondrial quality control by regulating genes associated with mitochondrial autophagy, such as PINK1 and Parkin, thereby ensuring that cells can maintain normal mitochondrial function in response to stress and injury (Timpani et al. 2024). These findings reveal estrogen’s importance in maintaining mitochondrial function and provide new ideas for treating diseases related to mitochondrial dysfunction.

Estrogenic Effects in Leber’s Hereditary Optic NeuropathyOverview of the Disease and Pathological Mechanisms

LHONs is an inherited optic neuropathy caused by a mutation in mitochondrial DNA that primarily affects retinal ganglion cells, resulting in vision loss. The most common mutations in LHON include m.11778G > A, m.3460G > A, and m.14484T > C, which typically cause dysfunction of the mitochondrial electron transport chain, which affects cellular energy production and metabolism, ultimately leading to degeneration of the optic nerve (Smimov 2022; Andreeva et al. 2023). The clinical presentation of LHON usually results in painless loss of vision in both eyes, and patients may experience a dramatic decrease in visual acuity over several weeks, often affecting the other eye shortly after losing sight in one eye (Hage and Vignal-Clermont 2021; Stramkauskaitė et al. 2022). Although the pathogenesis of LHON is not fully understood, studies have shown that mitochondrial dysfunction, oxidative stress, and apoptosis play an important role in the pathological process of LHON (Zanlonghi 2022; Priglinger 2023).

The Potential Role of Estrogen in Neuroprotection

The role of estrogen in the nervous system has received widespread attention, especially in neurodegenerative diseases like LHON. Studies have shown that estrogen has significant neuroprotective effects and can mitigate nerve damage through a variety of mechanisms. For example, estrogen can protect nerve cells by regulating mitochondrial function, inhibiting oxidative stress, and promoting the expression of nerve growth factors (Wang et al. 2022, 2023a). In early studies, it was found that in the nerve cell injury model, E2 pretreatment can significantly inhibit ATP depletion, suggesting that E2 can rapidly bind to ATPase and inhibit its activity, thereby reducing ATP hydrolysis (Guo et al. 2010). Estrogen can protect hippocampal neurons from damage caused by mitochondrial electron transport chain inhibitors, suggesting that it regulates the mitochondrial electron transport chain (Yao et al. 2011). Recently, estrogen has been shown to support the restoration of mitochondrial dynamics balance by enhancing the expression of OPA1, Mfn2, and p-Drp1 in the hippocampus. It also regulates mitophagy and eliminates damaged mitochondria by upregulating mitophagy-related proteins such as Beclin1 and LC3B and downregulating p62 while increasing the expression of Pink1 and Parkin (Hou et al. 2022).

Additionally, by upregulating ERβ, it activates the expression of NRF1 and its interaction with PGC1-α, promoting mitochondrial biogenesis in hippocampal neurons (Zhao et al. 2023). Ultimately, it reduces the accumulation of toxic proteins and improves cognitive function. Besides, estrogen may further enhance neuroprotective effects by influencing neuronal apoptotic pathways and inflammatory responses (Shvetcov et al. 2023; Youngblood et al. 2023). Specifically, overexpression of mitochondrial-targeted estrogen receptor beta (mtERβ) in neuroblastoma cells (N2A) can reduce the activation of caspase-9 and caspase-3. The presence of estrogen enhances the anti-apoptotic ability of this pathway, thereby increasing the cells’ resistance to apoptotic stimulation (Tsialtas et al. 2021). In patients with LHON, estrogen levels may affect disease progression and vision recovery, especially in women, in whom higher estrogen levels may have a protective effect on mitochondrial function (Zhong et al. 2019). Therefore, estrogen may become an important research direction in the treatment strategy of LHON patients, especially in the development of new neuroprotective treatment regimens, and the role of estrogen deserves further discussion.

The Association Between MELAS and EstrogenPathophysiological Characteristics of MELAS

MELAS syndrome is a genetic disorder caused by mutations in mitochondrial DNA, mainly affecting tissues with high energy needs, such as the brain and muscles. The most common mutation is mtDNA A3243G, which results in impaired mitochondrial transport RNA (tRNA) synthesis, affecting mitochondrial protein synthesis and energy production. This disorder of energy metabolism results in impaired cellular function and manifests in a variety of clinical symptoms, including stroke-like seizures, muscle weakness, recurrent headaches, and vomiting (Nikolaus et al. 2019; Fan et al. 2021). The pathophysiology of MELAS also includes increased oxidative stress and endothelial dysfunction, which may be associated with vascular lesions and multi-organ damage (Pek et al. 2019; Li et al. 2021). In addition, the joint radiographic misalignment of stroke-like lesions with vascular distribution in patients with MELAS and the possibility of persistent development of lesions over weeks or months provide essential clues to the diagnosis of MELAS (Bensaidane et al. 2020; Cheng et al. 2022). As a result, the pathophysiological profile of MELAS syndrome is complex, involving damage to multiple systems and metabolic abnormalities.

Regulatory Role of Estrogen on Oxidative Stress

Estrogen plays a vital role in maintaining cellular function and fighting oxidative stress. Studies have shown that estrogen can reduce levels of oxidative stress by activating estrogen receptors and regulating the expression of antioxidant enzymes (Gliemann and Hellsten 2019; Dharmani et al. 2019). In the process of MELAS, an increase in oxidative stress is strongly associated with mitochondrial dysfunction, which may exacerbate disease progression (Li et al. 2021; Balachandran Nair et al. 2021). Estrogen deficiency, such as in postmenopausal women, may lead to metabolic disorders and increased oxidative stress, which can exacerbate cardiovascular disease and other age-related diseases (Seals et al. 2019; Chainy and Sahoo 2020). In addition, estrogen may also affect the clinical presentation of MELAS patients by modulating endothelial cell function and improving vascular health (Mi et al. 2019; Tetsuka et al. 2021). Therefore, the role of estrogen in regulating oxidative stress is of great significance for understanding the pathological mechanism of MELAS syndrome and its potential therapeutic strategies.

The Effect of Estrogen on Mitochondrial Diseases in Two Sexes

The influence of estrogen on mitochondrial function and related disease processes exhibits notable sex-specific differences. For example, LHON is more prevalent in males. After the age of 5, the incidence rate in males is significantly higher than that in females, with a male-to-female ratio ranging from 2.92:1 to 4.8:1 (Poincenot et al. 2020; Lopez Sanchez et al. 2021). Moreover, males have an earlier onset. The median onset age for females is approximately 28.5–33 years, while for males, it is around 20–25 years (Rosenberg et al. 2016; Ji et al. 2022). The mechanism of the high prevalence of LHON in males is closely related to the difference in penetrance. Approximately 17.5–50% of males and 5.4–10% of females develop optic neuropathy (Yu-Wai-Man et al. 2009; Watson et al. 2023). Studies have shown that in the presence of mtDNA mutations, oxidative stress exacerbates mitochondrial dysfunction.

In contrast, estrogen can reduce penetrance in females by alleviating oxidative stress, making males more susceptible to the disease (Giordano et al. 2011). Secondly, the higher incidence of females in the field of neurodegenerative diseases suggests the potential influence of hormones, and the slow decline in male androgen levels may delay age-related mitochondrial and neurodegeneration (Huang et al. 2024). Menopause-related studies show that the incidence frequencies of LHON patients over 45 years old tend to be similar between sexes (Poincenot et al. 2020). In CPEO patients, females account for a higher proportion. Moreover, smoking has a significant negative impact on knee joint muscle strength in females, while males are unaffected (Heighton et al. 2019). This may confirm the regulatory window effect of hormonal homeostasis on mitochondrial health.

In summary, the interaction between sex hormones and mitochondrial function shapes sex-specific disease risks and aging processes. The increased risks of neurological diseases and premature death in early-menopausal women confirm the core role of hormonal homeostasis in maintaining mitochondrial health (McCarthy and Raval 2020). The sex differences in mitochondrial diseases are essentially the result of the combined effects of genetic transmission patterns, hormonal regulation, and aging mechanisms, which influence the incidence, clinical manifestations, and outcomes of the diseases.

Aging and Decline of Mitochondrial Function

Aging is a complex biological process, accompanied by a gradual decline in the function of cells and tissues, among which the decline of mitochondrial function is considered an important aging marker. Mitochondria are the energy factories of the cell that are responsible for the production of ATP and are involved in several metabolic processes. As we age, the structure and function of mitochondria undergo significant changes, including decreased oxidative phosphorylation capacity, increased ROS production, and accumulation of mitochondrial DNA mutations. These changes affect the energy metabolism of cells and may lead to apoptosis and dysfunction, which can accelerate the aging process. Studies have shown that mitochondrial decline is closely related to a variety of age-related diseases, such as neurodegenerative diseases, cardiovascular diseases, and metabolic syndrome. In addition, mitochondrial dynamics, such as fission and fusion, as well as mitophagy, also play a crucial role in maintaining mitochondrial health and function. Recently, interventions targeting mitochondrial function have been recognized as potential strategies to slow aging and improve health (Guo et al. 2023; Somasundaram et al. 2024).

Changes in Mitochondria During Aging

As aging progresses, mitochondria undergo various changes that profoundly impact cellular function and overall health. It has been found that aging mitochondria generally exhibit lower respiratory capacity and ATP production, accompanied by decreased mitochondrial membrane potential (Rosa et al. 2023). These changes affect mitochondrial energy metabolism and may also trigger oxidative stress within cells, leading to cell damage and apoptosis. In addition, mutations and damage to mitochondrial DNA accumulate during aging, further impacting the function of mitochondria and the metabolic state of cells (Fig. 1) (Kasapoğlu and Seli 2020; Miwa et al. 2022). Studies have also shown that mitochondrial dynamics, such as mitochondrial division and fusion, are affected during aging, leading to disruption of the mitochondrial network, which can exacerbate aging-related cellular dysfunction (Sharma et al. 2019). Therefore, understanding the changes in mitochondria during aging and their mechanisms is essential for developing intervention strategies for aging and related diseases.

Fig. 1

Estrogen’s impact on mitochondrial function during aging: Reduced estrogen affects mitochondrial respiratory chain complexes, reducing basal respiration, ATP production, and membrane potential while increasing ROS generation. It alters estrogen receptor interaction and mtDNA levels, leading to mitochondrial dysfunction, metabolic disorders, and cell damage

The Relationship among ROS, Mitochondria, and Aging

Mitochondria are not only the primary intracellular source of ROS but also play a crucial role in regulating the cellular antioxidant defense system (Zhang et al. 2025). ROS, as by-products of cellular metabolism, contribute to maintaining normal physiological functions at appropriate levels, such as regulating energy metabolism, signal transduction, and cell proliferation (Zhao et al. 2019). However, studies have shown that ultrastructural changes in senescent cells may be closely associated with the accumulation of excessive ROS (Alberico and Woods 2021). During the aging process, mitochondrial dysfunction disrupts the balance between the oxidation and antioxidant systems, leading to excessive ROS production. Due to the lack of histone protection in mtDNA, excessive ROS can oxidize and damage proteins and mtDNA, thereby exacerbating mitochondrial functional decline and forming a vicious cycle of ROS generation and mitochondrial damage (Ruder et al. 2008). Eventually, this leads to the loss of function and a decrease in the number of senescent cells. Meanwhile, the accumulated ROS can also reduce calcium ion storage in the mitochondrial matrix, trigger calcium ion fluctuations within mitochondria, disrupt redox homeostasis, increase the permeability of the outer mitochondrial membrane, and initiate apoptosis through the regulation of Bax family proteins (Basini and Grasselli 2015; Wolf et al. 2022). In the long term, mitochondrial dysfunction leads to ROS accumulation, which becomes a key driver of cell aging and accelerates the degradation of cellular functions.

Role of Estrogen in Aging-Related Mitochondrial Dysfunction

Estrogen plays a vital role in maintaining mitochondrial function and overall metabolic health. Studies have shown that estrogen affects cellular energy metabolism by regulating the expression of mitochondrial-related genes and promoting mitochondrial biosynthesis and function (Vernier and Giguère 2021; Wang et al. 2023b). During female aging, mitochondrial function tends to be significantly affected by a decline in estrogen levels, manifested by a decrease in mitochondria’s ability to produce energy and an increase in oxidative stress (Moreira-Pais et al. 2024). When estrogen levels decrease, the function of SIRTs is also affected. SIRT3 significantly reduces mitochondrial ROS by deacetylating and activating SOD2, thereby protecting the mitochondria from oxidative damage (Zhao et al. 2025). Estrogen can inhibit the opening of the mitochondrial permeability transition pore, thereby preventing ROS accumulation and protecting the integrity of the mitochondrial outer membrane, which in turn prevents cellular damage (Parodi-Rullán et al. 2018). In addition, estrogen also helps clear damaged mitochondria by regulating mitophagy and dynamic changes, thereby maintaining the metabolic homeostasis of cells (Vernier and Giguère 2021; Moreau et al. 2024). Therefore, interventions targeting estrogen signaling pathways may provide new therapeutic ideas for improving aging-related mitochondrial dysfunction. Researchers are exploring estrogen supplementation or its analogs to improve mitochondrial function and metabolic health in aging women (Kasapoğlu and Seli 2020). This strategy may help slow aging and reduce the risk of aging-related diseases.

Interaction of Mitophagy with EstrogenMechanisms of Mitophagy and Its Importance

Mitophagy is the process by which cells selectively remove damaged or excess mitochondria and is essential for maintaining the quality and function of mitochondria within cells. Mitochondria are the energy factories of cells, and their normal function directly affects the metabolism, energy supply, and survival of cells. Mitophagy is a complex process involving multiple pathways and mechanisms, mainly including ubiquitin-dependent and non-ubiquitin-dependent pathways. The mechanism of mitophagy largely depends on specific signaling pathways. The classic ubiquitin-dependent pathway, such as the PINK1/Parkin pathway, promotes their degradation by identifying damaged mitochondria and recruiting mitophagosomes (Lazarou et al. 2015). On the outer mitochondrial membrane, there are many proteins containing LC3-interacting regions. As mitophagy receptors, they can directly bind to LC3 without ubiquitination. For example, under ischemia-hypoxia conditions, the upregulated expression of NIX/BNIP3 can directly bind to damaged mitochondria and interact with LC3 to promote mitophagy (Chen et al. 2021). During mitochondrial network remodeling in oligodendrocyte differentiation, dimerized BNIP3L directly induces mitophagy as a mitophagy receptor (Marinković et al. 2021). Besides, the LC3-binding affinity of FUNDC1 increases with the severity of hypoxia. After phosphorylation, it interacts with LC3 and initiates mitophagy (Liu et al. 2012). Studies have shown that dysregulation of mitophagy is closely related to various diseases, including neurodegenerative diseases, cardiovascular diseases, and cancer (Towers et al. 2021; Wang et al. 2024). In these pathological states, the accumulation of damaged mitochondria increases oxidative stress, which triggers apoptosis and inflammatory responses. Therefore, promoting mitophagy is a potential therapeutic strategy to improve cellular health and slow aging by restoring mitochondrial function (Tan et al. 2019; Liu et al. 2023).

Regulatory Role of Estrogen in Mitophagy and Its Clinical Significance

Estrogens, especially E2, are important in regulating mitophagy. Studies have found that E2 can enhance mitophagy by activating the SIRT1/LKB1/AMPK/Ulk1 signaling pathway (Fig. 2), thereby delaying cell senescence and maintaining mitochondrial function (Sasaki et al. 2021). The phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway is a fundamental regulator of cellular metabolism, growth, and survival, and it plays a pivotal role in mediating estrogen’s effects on mitochondrial autophagy. Estrogen activates this pathway through its receptors, enhancing cell survival and metabolic regulation. Studies have shown that estrogen treatment can restore the balance of cardiac autophagy and mitochondrial dynamics in ovariectomized rats, which indicates its’ cardioprotective effects (Gowayed et al. 2024). Furthermore, estrogen’s PI3K/Akt pathway activation has been linked to increased mitochondrial biogenesis and improved cellular metabolism, particularly in cardiovascular health (Sasaki et al. 2021). The pathway’s role in promoting autophagy is underscored by its interaction with downstream effectors that regulate mitochondrial homeostasis, thereby preventing cellular senescence and dysfunction (Tao and Cheng 2023). The AMP-activated protein kinase (AMPK) signaling pathway is a key regulator of cellular energy homeostasis and is significantly influenced by estrogen. AMPK activation promotes autophagy and mitochondrial biogenesis, enhancing cellular resilience to stress conditions. Estrogen has been found to activate AMPK, leading to improved mitochondrial function and reduced apoptosis in various cell types (He et al.