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Mitochondrial dysfunction in perimenopausal mood disorders: From hormonal shifts to neuroenergetic failure (Review)

  • Authors:
    • Yang Yu
    • Han Yapeng
    • Zelin Liu
    • Lei Fang
    • Jianuo Li
    • Yifeng Luan
    • Wenzhong Li
    • Huifang Cong
    • Xiuhong Wu
  • View Affiliations / Copyright

    Affiliations: Department of Second Clinical Medical School, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang 150040, P.R. China, Department of Acupuncture, First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang 150000, P.R. China, Department of Orthopedics, The Second Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang 150001, P.R. China, Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China, Department of Basic Medical Sciences, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang 150040, P.R. China, Department of Gynecology, The Second Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang 150040, P.R. China, School of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang 150040, P.R. China
    Copyright: © Yu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 215
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    Published online on: October 1, 2025
       https://doi.org/10.3892/ijmm.2025.5656
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Abstract

Perimenopause represents a key transition from a reproductive to non‑reproductive state in women, characterized by physiological and psychological changes. Mood disturbances during this period, such as depression, anxiety and cognitive decline, are increasingly understood as complex neuroendocrine and metabolic disorders. Mitochondrial homeostasis carries out a key role in the pathophysiology of these affective symptoms. Disruptions in mitochondrial biogenesis, mitophagy and calcium regulation contribute to synaptic dysfunction and neuroimmune changes. These mitochondrial alterations interact with inflammatory pathways and hormonal signals, exacerbating neuropsychiatric symptoms. A more comprehensive understanding of the molecular mechanisms of mitochondrial dysfunction in menopausal mood disorders unveils potential therapeutic strategies, including mitochondria‑targeted antioxidants, hormone replacement therapy, and lifestyle interventions designed to restore mitochondrial integrity and cerebral bioenergetic function.
View Figures

Figure 1

Key mitochondrial processes in
neuronal homeostasis. Mitochondrial Ca2+ uptake via VDAC
and the MCU complex activates TCA cycle dehydrogenases (PDH,
isocitrate dehydrogenase and α-KG dehydrogenase), promoting
NADH/flavin adenine dinucleotide (reduced form) production and ATP
synthesis. Electron leakage from complexes I/III generates
superoxide (O2−•), converted to
H2O2 and detoxified by antioxidant systems
(superoxide dismutase 2, GPX, PRDX, TRX and GSH). Excess ROS
triggers mPTP opening, cyt c release and apoptosis.
Glutamate is synthesized from α-ketoglutarate via GDH or
transaminases, supporting neurotransmission and nitrogen
metabolism. E2 enhances bioenergetics and antioxidant defense (red
arrows), while inhibiting ROS and apoptosis (green arrows). α-KG,
α-ketoglutarate; ATP, adenosine triphosphate; Ca2+,
calcium ion; Cyt c, cytochrome c; E2, 17β-estradiol;
GDH, glutamate dehydrogenase; GPX, glutathione peroxidase; GSH,
reduced glutathione; H2O2, hydrogen peroxide;
MCU, mitochondrial calcium uniporter; mPTP, mitochondrial
permeability transition pore; NADH, nicotinamide adenine
dinucleotide (reduced form); O2−•, superoxide
anion radical; PDH, pyruvate dehydrogenase; PRDX, peroxiredoxin;
ROS, reactive oxygen species; SOD2, superoxide dismutase 2; TCA
cycle, tricarboxylic acid cycle; TRX, thioredoxin; VDAC,
voltage-dependent anion channel.

Figure 2

Estrogenic regulation of
mitochondrial function. E2 engages ERα and ERβ to regulate
mitochondrial function via genomic and non-genomic pathways. ERβ is
mainly located in mitochondria in neurons, while ERα shows
predominant nuclear expression in astrocytes. Genomically, it
upregulates TFAM and antioxidant enzymes (SOD2, GPx and catalase),
enhancing oxidative phosphorylation and redox balance.
Non-genomically, E2 stabilizes mitochondrial dynamics (↑Mfn1/2,
OPA1 and ↓Drp1) and promotes mitophagy via ERβ-FUNDC1 signaling.
Drp1, dynamin-related protein 1; E2, 17β-estradiol; ERα, estrogen
receptor α; ERβ, estrogen receptor β; FUNDC1, FUN14 domain
containing 1; GPx, glutathione peroxidase; Mfn1/2, mitofusin 1/2;
OPA1, optic atrophy 1; SOD2, superoxide dismutase 2; TFAM,
transcription factor A, mitochondrial.

Figure 3

Disruption of the
hormone-mitochondria-mood axis in estrogen deficiency. Estrogen
deficiency induces multifaceted mitochondrial dysfunction in
mood-regulating brain regions, characterized by impaired oxidative
phosphorylation, reduced ATP synthesis, excessive reactive oxygen
species accumulation, dysregulated fission-fusion dynamics and
suppressed mitophagy. These alterations compromise neuronal
bioenergetic capacity and redox homeostasis, contributing to
synaptic dysfunction and neuroinflammatory cascades. This
mechanistic continuum constitutes the hormone-mitochondria-mood
axis, wherein endocrine withdrawal drives mitochondrial
destabilization, ultimately predisposing individuals to affective
and cognitive disturbances during the perimenopausal transition.
ATP, adenosine triphosphate; Ca2+, calcium ion; COX,
cytochrome c oxidase (complex IV); E2, 17β-estradiol; ETC, electron
transport chain; GABA, gamma-aminobutyric acid; GPX, glutathione
peroxidase; GSH, reduced glutathione; MCU, mitochondrial calcium
uniporter; mPTP, mitochondrial permeability transition pore; NRF1,
nuclear respiratory factor 1; Parkin, Parkin RBR E3 ubiquitin
protein ligase; PGC-1α, peroxisome proliferator-activated receptor
gamma coactivator 1-α; PINK1, PTEN-induced putative kinase 1; ROS,
reactive oxygen species; SOD2, superoxide dismutase 2; TCA,
tricarboxylic acid cycle; TFAM, transcription factor A,
mitochondrial.
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Copy and paste a formatted citation
Spandidos Publications style
Yu Y, Yapeng H, Liu Z, Fang L, Li J, Luan Y, Li W, Cong H and Wu X: Mitochondrial dysfunction in perimenopausal mood disorders: From hormonal shifts to neuroenergetic failure (Review). Int J Mol Med 56: 215, 2025.
APA
Yu, Y., Yapeng, H., Liu, Z., Fang, L., Li, J., Luan, Y. ... Wu, X. (2025). Mitochondrial dysfunction in perimenopausal mood disorders: From hormonal shifts to neuroenergetic failure (Review). International Journal of Molecular Medicine, 56, 215. https://doi.org/10.3892/ijmm.2025.5656
MLA
Yu, Y., Yapeng, H., Liu, Z., Fang, L., Li, J., Luan, Y., Li, W., Cong, H., Wu, X."Mitochondrial dysfunction in perimenopausal mood disorders: From hormonal shifts to neuroenergetic failure (Review)". International Journal of Molecular Medicine 56.6 (2025): 215.
Chicago
Yu, Y., Yapeng, H., Liu, Z., Fang, L., Li, J., Luan, Y., Li, W., Cong, H., Wu, X."Mitochondrial dysfunction in perimenopausal mood disorders: From hormonal shifts to neuroenergetic failure (Review)". International Journal of Molecular Medicine 56, no. 6 (2025): 215. https://doi.org/10.3892/ijmm.2025.5656
Copy and paste a formatted citation
x
Spandidos Publications style
Yu Y, Yapeng H, Liu Z, Fang L, Li J, Luan Y, Li W, Cong H and Wu X: Mitochondrial dysfunction in perimenopausal mood disorders: From hormonal shifts to neuroenergetic failure (Review). Int J Mol Med 56: 215, 2025.
APA
Yu, Y., Yapeng, H., Liu, Z., Fang, L., Li, J., Luan, Y. ... Wu, X. (2025). Mitochondrial dysfunction in perimenopausal mood disorders: From hormonal shifts to neuroenergetic failure (Review). International Journal of Molecular Medicine, 56, 215. https://doi.org/10.3892/ijmm.2025.5656
MLA
Yu, Y., Yapeng, H., Liu, Z., Fang, L., Li, J., Luan, Y., Li, W., Cong, H., Wu, X."Mitochondrial dysfunction in perimenopausal mood disorders: From hormonal shifts to neuroenergetic failure (Review)". International Journal of Molecular Medicine 56.6 (2025): 215.
Chicago
Yu, Y., Yapeng, H., Liu, Z., Fang, L., Li, J., Luan, Y., Li, W., Cong, H., Wu, X."Mitochondrial dysfunction in perimenopausal mood disorders: From hormonal shifts to neuroenergetic failure (Review)". International Journal of Molecular Medicine 56, no. 6 (2025): 215. https://doi.org/10.3892/ijmm.2025.5656
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