Mitochondrial organization in rod and cone photoreceptors and intercellular mitochondrial material transfer in models of blinding disease

Abstract Photoreceptors are among the most metabolically active neurons and rely on a highly specialized mitochondrial network to support phototransduction, outer segment renewal, calcium homeostasis, and synaptic transmission. Here, we established and used robust tools for visualizing and tracking mitochondrial populations in rod and cone photoreceptors of wildtype mice and four retinal degeneration models. Using a Cre-dependent mito-Dendra2 mouse line and adeno-associated virus (AAV)-mediated cell type-specific mitochondrial reporters, we characterized the mitochondrial architecture of both photoreceptor types. Rods contained three major mitochondrial pools located in the inner segment, soma, and synaptic terminal. Cones displayed a more complex organization, including elongated mitochondria in the inner segment, a juxtanuclear mitochondrial cap, a characteristic rounded mitochondrion basal to the nucleus, and small mitochondria within pedicles. Application of these reporters to inherited retinal degeneration models with rod- or cone-specific mutations revealed photoreceptor-derived fluorescent material within Müller glial cells. The reporters also pointed to changes in the mitochondrial appearance and to spatial disorganization in affected photoreceptors, linking altered mitochondrial architecture to degeneration. These tools enable detailed visualization of rod- and cone-specific mitochondrial populations and may facilitate evaluation of mitochondria-targeted therapies for blinding retinal diseases.