Mitochondrial transplantation: a promising strategy for the treatment of retinal degenerative diseases

Abstract

The retina, a crucial neural tissue, is responsible for transforming light signals into visual information, a process that necessitates a significant amount of energy. Mitochondria, the primary powerhouses of the cell, play an integral role in retinal physiology by fulfilling the high-energy requirements of photoreceptors and secondary neurons through oxidative phosphorylation. In a healthy state, mitochondria ensure proper visual function by facilitating efficient conversion and transduction of visual signals. However, in retinal degenerative diseases, mitochondrial dysfunction significantly contributes to disease progression, involving a decline in membrane potential, the occurrence of DNA mutations, increased oxidative stress, and imbalances in quality-control mechanisms. These abnormalities lead to an inadequate energy supply, the exacerbation of oxidative damage, and the activation of cell death pathways, ultimately resulting in neuronal injury and dysfunction in the retina. Mitochondrial transplantation has emerged as a promising strategy for addressing these challenges. This procedure aims to restore metabolic activity and function in compromised cells through the introduction of healthy mitochondria, thereby enhancing the cellular energy production capacity and offering new strategies for the treatment of retinal degenerative diseases. Although mitochondrial transplantation presents operational and safety challenges that require further investigation, it has demonstrated potential for reviving the vitality of retinal neurons. This review offers a comprehensive examination of the principles and techniques underlying mitochondrial transplantation and its prospects for application in retinal degenerative diseases, while also delving into the associated technical and safety challenges, thereby providing references and insights for future research and treatment.

Figure 1

The timeline of the development of mitochondrial transplantation as a treatment for retinal degenerative diseases.

Figure 2

The current status of mitochondrial transplantation for the treatment of retinal degenerative diseases. This article summarizes the research status from several aspects, including natural pathways of mitochondrial transfer, artificial mitochondrial transplantation pathways, and the role of mitochondrial transplantation in the treatment of retinal degenerative diseases. Finally, the challenges and limitations faced by mitochondrial transplantation as a treatment method were summarized. Create with BioRender.com.

Figure 3

Mitochondrial abnormalities in retinal degenerative diseases. In age-related macular degeneration (AMD), mitochondria undergo abnormal changes due to oxidative stress and DNA damage, leading to reduced ATP synthesis and increased free radical production. In glaucoma, retinal ganglion cells (RGCs) are affected by oxidative stress, resulting in excessive reactive oxygen species (ROS) production by mitochondria, causing damage to cellular DNA, proteins, and lipids. There is an imbalance in mitochondrial dynamics in glaucoma, characterized by the upregulation of the expression of the fission protein Drp1 and the downregulation of that of the fusion proteins Mfn1/2 and OPA1, causing mitochondrial network fragmentation and further weakening mitochondrial energy synthesis capabilities. In Leber’s hereditary optic neuropathy (LHON) and pigmentary retinopathy (PR), pathogenesis is closely related to specific point mutations in mitochondrial DNA (mtDNA), typically located in genes encoding subunits of complex I (NADH dehydrogenase) of the electron transport chain. Meanwhile, mutations in the OPA1 gene are a key pathogenic feature of dominant optic atrophy (DOA). Created with BioRender.com.

Figure 4

Natural pathways of mitochondrial transfer between cells. (A) Endocytosis is the cellular process via which cells internalize extracellular substances by enveloping them with their plasma membrane. (B) Tunnelling nanotubes (TNTs) are slender tubular connections formed between cells that allow for the direct transcellular exchange of materials, including mitochondria. (C) Gap junction channels are hexameric structures composed of connexin proteins. Cells transfer mitochondria between each other through these channels. Created with BioRender.com.

Figure 5

Mitochondrial transplantation targeting retinal diseases. Mitochondria are extracted from pluripotent stem cells and tissues. In vivo experiments, such as implantation through intravitreal injection or subretinal injection, among other methods, can improve the mitochondrial impairment-induced structural and functional damage in RGCs, photoreceptors, retinal pigment epithelium (RPE), and optic nerve. Created with BioRender.com. iPSC: Induced pluripotent stem cell; MSCs: mesenchymal stem cells; RGCs: retinal ganglion cells.

Figure 6

Difficulties and challenges in mitochondrial transplantation. Mitochondrial transplantation faces a variety of challenges, such as the technical complexity of intraocular injections, limitations in the survival rate of transplanted mitochondria, the risk of immune rejection, and moral and ethical issues. Created with BioRender.com.