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Updated: Jun 27, 2025
Assessing Mitochondrial Function in Sciatic Nerve by High-Resolution Respirometry
Published on: May 5, 2022
Mfn2 regulates mitochondria and mitochondria-associated endoplasmic reticulum membrane function in neurodegeneration
Ruilou Zhu1, Lu Liu2, Tian Mao3
1Department of Anesthesiology and Perioperative Medicine, Center for Clinical Single Cell Biomedicine, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, Henan, PR China 450003.
Abstract:
Repeated sevoflurane exposure in neonatal mice can leads to neuronal apoptosis and mitochondrial dysfunction. The mitochondria are responsible for energy production to maintain homeostasis in the central nervous system. The mitochondria-associated endoplasmic reticulum membrane (MAM) is located between the mitochondria and endoplasmic reticulum (ER), and it is critical for mitochondrial function and cell survival. MAM malfunction contributes to neurodegeneration, however, whether it is involved in sevoflurane-induced neurotoxicity remains unknown. Our study demonstrated that repeated sevoflurane exposure induced mitochondrial dysfunction and dampened the MAM structure. The upregulated ER-mitochondria tethering enhanced Ca2+ transition from the cytosol to the mitochondria. Overload of mitochondrial Ca2+ contributed to opening of the mitochondrial permeability transition pore (mPTP), which caused neuronal apoptosis. Mitofusin 2(Mfn2), a key regulator of ER-mitochondria contacts, was found to be suppressed after repeated sevoflurane exposure, while restoration of Mfn2 expression alleviated cognitive dysfunction due to repeated sevoflurane exposure in the adult mice. These evidences suggest that sevoflurane-induced MAM malfunction is vulnerable to Mfn2 suppression, and the enhanced ER-mitochondria contacts promotes mitochondrial Ca2+ overload, contributing to mPTP opening and neuronal apoptosis. This paper sheds light on a novel mechanism of sevoflurane-induced neurotoxicity. Furthermore, targeting Mfn2-mediated regulation of the MAM structure and mitochondrial function may provide a therapeutic advantage in sevoflurane-induced neurodegeneration.
Insights
Repeated sevoflurane exposure harms neonatal brain cells by disrupting mitochondria and the mitochondria-associated endoplasmic reticulum membrane (MAM). Targeting Mfn2 may protect against this neurotoxicity.
Area of Science:
- Neuroscience
- Cell Biology
- Anesthesiology
Background:
- Mitochondrial dysfunction and neuronal apoptosis are consequences of repeated sevoflurane exposure.
- Mitochondria-associated endoplasmic reticulum membrane (MAM) is crucial for mitochondrial function and cell survival.
- The role of MAM in sevoflurane-induced neurotoxicity is currently unknown.
Purpose of the Study:
- To investigate the involvement of MAM in sevoflurane-induced neurotoxicity.
- To elucidate the underlying molecular mechanisms of sevoflurane neurotoxicity.
- To explore potential therapeutic targets for sevoflurane-induced neurodegeneration.
Main Methods:
- Neonatal mice were exposed to repeated sevoflurane anesthesia.
- Mitochondrial function, MAM structure, and ER-mitochondria tethering were assessed.
- Calcium (Ca2+) transition, mitochondrial permeability transition pore (mPTP) opening, and neuronal apoptosis were analyzed.
- Mitofusin 2 (Mfn2) expression was modulated, and its effect on cognitive function was evaluated in adult mice.
Main Results:
- Repeated sevoflurane exposure induced mitochondrial dysfunction and impaired MAM structure.
- Enhanced ER-mitochondria tethering led to increased cytosolic Ca2+ transition to mitochondria.
- Mitochondrial Ca2+ overload promoted mPTP opening and neuronal apoptosis.
- Sevoflurane exposure suppressed Mfn2 expression; Mfn2 restoration alleviated cognitive deficits.
Conclusions:
- Sevoflurane-induced neurotoxicity involves MAM malfunction, exacerbated by Mfn2 suppression.
- Enhanced ER-mitochondria contacts promote mitochondrial Ca2+ overload, mPTP opening, and neuronal apoptosis.
- Targeting Mfn2-mediated MAM regulation offers a potential therapeutic strategy against sevoflurane-induced neurodegeneration.
