Axonal mitophagy in retinal ganglion cells

Liang et al. Cell Communication and Signaling https://doi.org/10.1186/s12964-024-01761-0 (2024) 22:382 Cell Communication and Signaling Open Access REVIEW Axonal mitophagy in retinal ganglion cells Yang Liang1, Yulin Li1, Qing Jiao1, Muyang Wei1, Yan Wang1, Aoteng Cui1, Zhihui Li1 and Guangyu Li1* Abstract Neurons, exhibiting unique polarized structures, rely primarily on the mitochondrial production of ATP to maintain their hypermetabolic energy requirements. To maintain a normal energy supply, mitochondria are transported to the distal end of the axon. When mitochondria within the axon are critically damaged beyond their compensatory capacity, they are cleared via autophagosomal phagocytosis, and the degradation products are recycled to replenish energy. When the mitochondria are dysfunctional or their transport processes are blocked, axons become susceptible to degeneration triggered by energy depletion, resulting in neurodegenerative diseases. As the final checkpoint for mitochondrial quality control, axonal mitophagy is vital for neuronal growth, development, injury, and regeneration. Furthermore, abnormal axonal mitophagy is crucial in the pathogenesis of optic nerve-related diseases such as glaucoma. We review recent studies on axonal mitophagy and summarize the progress of research on axonal mitophagy in optic nerve-related diseases to provide insights into diseases associated with axonal damage in optic ganglion cells. Keywords Mitophagy, Axon, Optic nerve, Energy Introduction Neurons primarily depend on mitochondrial oxidative phosphorylation to provide ATP for their energy requirements. Retinal ganglion cells (RGCs) with complex dendrites and significantly longer axonal structures have relatively higher energy requirements. Furthermore, mitochondria are involved in various physiological processes in RGCs, such as maintaining metabolic balance, regulating intracellular calcium levels, generating reactive oxygen species (ROS), and mediating apoptotic signaling [1–3]. Hence, preserving mitochondrial quality is critical for sustaining energy balance and ensuring normal physiological functioning in RGCs. Autophagy is a critical degradative pathway for eukaryotic cells, important for the clearance of aggregated *Correspondence: Guangyu Li 1 Department of Ophthalmology, Second Hospital of Jilin University, Changchun 130041, China proteins and dysfunctional organelles, and is an essential homeostatic mechanism for neurons [4]. Specifically, mitochondrial autophagy, or mitophagy, is a specialized form of autophagy that targets mitochondria. Mitophagy removes and recycles damaged mitochondria and regulates the biogenesis of new, fully functional ones preserving healthy mitochondrial functions and activities [5]. This process helps to prevent the accumulation of defective mitochondria which can lead to cellular stress and various diseases [6, 7]. Under normal physiological conditions, important macromolecular precursors are produced through mitochondrial autophagy to replenish cells while preventing the accumulation of dead and dysfunctional mitochondria. Due to their polarized structure, mitochondria must be transported in RGCs through long axons and terminals to meet high energy demands and maintain energy homeostasis. The maintenance of axonal mitochondrial quality is primarily accomplished through mitochondrial biosynthesis, fission and fusion, bidirectional transport, and clearance. Mitophagy modulates mitochondrial mass in axons and © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it.The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.To view a copy of this licence, visit http:// creativecommons.org/licenses/by-nc-nd/4.0/. Liang et al. Cell Communication and Signaling (2024) 22:382 clears senescent and damaged mitochondria. Autophagosomes in the axons transport engulfed mitochondria to the soma to complete the autophagy process [8, 9]. Ashrafi et al. demonstrated that localized mitophagy in distal axons is mediated by PINK1-Parkin [10]. The process of axonal mitophagy is complex, and its mechanism has not been fully elucidated. Various studies have shown that impaired regulation of neuronal mitophagy leads to axonal degeneration and synaptic instability, which are associated with neurodegenerative diseases, including Alzheimer disease, Huntington disease, Parkinson disease (PD), and amyotrophic lateral sclerosis [11–17]. Regulation of mitophagy is a potential target for the treatment of neurodegenerative diseases. Two crucial genes, Pink1 and Parkin, have been identified in hereditary PD, playing a significant role in maintaining mitochondrial integrity [18], as well as facilitating the process of local mitophagy at the distal axon [10, 19]. Furthermore, diseases associated with axonal damage in RGCs, such as glaucoma, are inextricably linked to axonal mitophagy [20–24]. We review recent studies on axonal mitophagy and summarize the progress of research on axonal mitophagy in optic nerve-related diseases, which are intended to provide insights into diseases associated with axonal damage in RGC. Mitochondrial biogenesis and transport in RGC axons In most mammalian species, the axons of RGCs within the retina are unmyelinated. However, they extend centripetally along the lamina cibrosa to the optic nerve head (ONH), where they converge and make a turn at right angles to form the optic nerve; they are myelinated in the retrolaminar region of the ONH, and the morphology is maintained through the rest of the optic nerve [25, 26]. Most mitochondria are located in the axons of RGCs since the axon length is at least three orders of magnitude greater than the soma diameter [26, 27]. A high density of mitochondria is required in the unmyelinated regions of RGC axons, nodes of Ranvier, and synaptic terminals to support the high energy demands of nerve fiber conduction and neurotransmitter release [28–30]. Because RGCs possess longer axons compared to other neurons, the distribution and consumption of intracellular energy are not homogeneous [26]. However, the diffusion capacity of ATP in the cytoplasm is limited, therefore, (...truncated)