Mitofusins are required for specialized mitochondrial morphology and function of rod photoreceptor cells.

Mitochondria are dynamic organelles that undergo continuous morphological changes, yet exhibit unique, cell-type-specific structures. In rod photoreceptor cells of the retina, these include elongated mitochondria in the inner segments and a distinct, large, circular mitochondrion within each presynaptic terminal. The mechanisms underlying the establishment and maintenance of these specialized mitochondrial morphologies, as well as their relationship to photoreceptor function, remain incompletely understood. Here, we investigated the roles of mitochondrial fusion proteins mitofusin 1 (MFN1) and mitofusin 2 (MFN2) in rod photoreceptor cells. Rod-specific ablation of MFN1 and MFN2 resulted in near-complete and uniform mitochondrial fragmentation by 1 month of age, indicating that mitochondrial fusion is required for the development and maintenance of photoreceptor cell-specific mitochondrial architecture. At this stage, the layer structures of the retina examined by light microscopy appeared largely unaffected. Despite the absence of overt structural degeneration, electroretinography revealed early functional impairment, including reduced a-wave amplitudes and attenuation of the c-wave, indicating compromised rod photoreceptor activity and disrupted photoreceptor-RPE interactions. This was followed by progressive photoreceptor cell degeneration observed at 2 and 3 months of age. MFN1/2 ablation was also associated with changes in proteins involved in glycolysis, oxidative phosphorylation, and β-oxidation, along with activation of cellular stress pathways, including ER stress and the unfolded protein response. While total retinal ATP levels were only modestly reduced at early stages, these findings are consistent with alterations in metabolic homeostasis. Together, our findings demonstrate that MFN1 and MFN2 are required for specialized mitochondrial architecture in rod photoreceptor cells, and that their loss is associated with molecular remodeling and early functional deficits, preceding progressive degeneration.