Abstract
Purpose :
Intercelllular mitochondrial transfer has been reported across a variety of cells and tissues under both physiological and pathological conditions. Such transfer, and even mitochondrial transplantation, has shown broad therapeutic potential. The effectiveness of this therapy, however, is limited by a lack of understanding of the cellular and molecular mechanisms. Here, we report the ultrastructural features of mitochondrial transfer between inner retinal neurons discovered through retinal connectomics analysis.
Methods :
Retinal Connectome 2 (RC2) was built by automated transmission electron microscopy at ultrastructural (2nm/pixel) resolution, enabling detection and ultrastructural visualization of material transfer across neuronal membranes. RC2 is a 0.25mm diameter volume of retina obtained from a 5 month old female C57BL/6J mouse. The Viking application was used to visualize and annotate inter- and intracellular features of interest in the connectome.
Results :
Exploration of RC2 revealed material transfer between apposing neural processes within the OFF sublamina of the inner plexiform layer. The transferred material can be defined as a mitochondria, confirmed by the presence of cristae. At the transfer site, a short, electron-dense 140-nm diameter tube with a curved cap tightly associated with the inner mitochondrial membrane of one neurite extends into a vacuole within the apposing neurite formed by the plasma membranes of the two cells. Thin cytoskeletal components consistent with actin microfilaments extend into the mitochondrion. Morphology and synaptology of the acceptor cell confirm it is an Aii amacrine cell, while preliminary findings suggest the donor cell is a type of ON/OFF ganglion cell.
Conclusions :
While the prevalence remains unclear, these findings demonstrate active mitochondrial transfer between different classes of endogenous inner retinal neurons and suggests intercellular mitochondrial transfer between neurons may represent an important component of tissue homeostasis in the retina. The features of this transfer differ from that seen in previously reported mitochondrial transfer between photoreceptors upon transplantation, which may indicate cell type- or context-dependent differences in the cellular or molecular mechanisms. Understanding the mechanisms underlying physiological mitochondrial transfer could serve as a catalyst for development of novel therapeutics for disease in the retina and beyond.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.