In a recent review published in Genes & Diseases, researchers from the Yunnan Key Laboratory of Laboratory Medicine, Yunnan Province Clinical Research Center for Laboratory Medicine, the First Affiliated Hospital of Kunming Medical University and the First People’s Hospital of Lushui City explore the mechanisms underlying mitochondrial dysfunction in lung disease and the potential application of mitochondrial transplantation (MT) for its treatment.

The authors describe the various processes leading to mitochondrial dysfunction in lung diseases, including (i) susceptibility to oxidative stress and DNA damage and (ii) mitochondrial DNA (mtDNA) damage and inflammatory escape. These latter processes involve a high rate of mutations in mtDNA and activation of the NLRP3 inflammasome (leading to IL-1β and IL-18 release) and the cGAS-STING pathways (inducing type I interferons).

MT is an innovative therapeutic approach involving the transfer of functional, intact mitochondria from a healthy source into host cells or tissues that have dysfunctional mitochondria, with the aim of restoring cellular energy metabolism, enhancing mitochondrial function, and preventing cell death in affected tissues. This approach has demonstrated good efficacy in ischemia-reperfusion injury, Parkinson’s disease (PD), breast cancer, and lung disease animal models.
Intercellular mitochondrial transfer occurs through (i) tunneling nanotubes (TNTs), (ii) extracellular vesicles, (iii) mitochondrial extrusion, and (iv) gap-junction channels. The review also discusses the various sources and isolation methods for mitochondria used in transplantation.

Mitochondrial transplantation therapy (MTT) holds significant promise for a wide range of lung diseases, including conditions such as COPD, asthma, and ALI/ARDS, because mitochondrial dysfunction plays a critical role in their pathogenesis.
Preclinical studies demonstrate that MTT and the underlying mechanism of intercellular mitochondrial transfer effectively mitigate lung pathology. In COPD and asthma, diseases characterized by inflammation and oxidative stress, MTT transfer was shown to repair injured epithelial cells and restore homeostasis. In severe conditions such as ALI/ARDS and lung ischemia-reperfusion injury (LIRI), MTT reduces endothelial damage, improves gas exchange, and counteracts the powerful inflammatory response triggered by escaping mitochondrial DNA (DAMPs).

Furthermore, MTT shows therapeutic efficacy in vascular diseases such as pulmonary hypertension (PH) by reversing vascular remodeling and increasing ATP levels. Similarly, in pulmonary fibrosis (PF), exogenous mitochondria are preferentially directed to and taken up by damaged cells, leading to a reduction in fibrotic areas.
On the contrary, the role of MTT in lung cancer is complex; though it can induce cancer cell apoptosis by reversing dysfunction, some studies indicate that mitochondrial transfer may promote tumor progression, necessitating further research.

However, MTT technology faces certain drawbacks, including challenges in viability maintenance (necessitating improved preservation methods) and immunogenicity. Additionally, while autologous MTT (using the patient’s own cells) is considered safer, the use of allogeneic MTT (from a donor) remains controversial, warranting further research. Finally, although direct evidence is pending, the success of MTT in reversing mitochondrial dysfunction in other aging models suggests a strong potential to restore function and combat senescence in the aged lung.

In conclusion, this review provides an extensive overview of mitochondrial dysfunction in lung diseases and discusses the feasibility of MT as a promising therapeutic strategy in the treatment of lung diseases.

Reference

Title of the original paper
Mitochondrial Transplantation in Lung Diseases: From mechanisms to application prospects

Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI: https://doi.org/10.1016/j.gendis.2025.101856

Funding Information:

• Applied Basic Research Foundation of Yunnan Province, China (No. 202301AY070001-183)
• Kunming Medical University, China (No. 2024S245)

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.

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