Role of mitochondrial dynamics in rod photoreceptor cells

University Of Wisconsin-Madison, Madison WI

Investigators

Abstract

Abstract Mitochondria, the energy generating organelles, dynamically fuse and fission to take various forms in different cells. Mitochondrial dynamics have been linked to complex cellular processes such as metabolism, immune response, and cell death, but the exact relations between their form and function are still not fully understood. Retinal rod photoreceptor cells, the energy intensive neurons, provide an excellent model for investigating the significance of mitochondrial form because they have a uniquely uniform arrangement of elongated mitochondria in the inner segments and one large circular mitochondrion in each of the presynaptic terminals. In our preliminary study, rod photoreceptor cell-specific ablation of mitochondrial fusion proteins, mitofusin 1 (MFN1) and mitofusin 2 (MFN2), resulted in fragmentation of mitochondria by one month of age, followed by extensive photoreceptor cell degeneration by the adult age. In addition, rod photoreceptor cell- specific ablation of a mitochondrial fission factor, dynamin-related protein 1 (DRP1) caused late-onset and age- dependent retinal degeneration (obvious by one year of age), suggesting the role of DRP1 in aging rod photoreceptor cells. Therefore, we hypothesize that development and maintenance of the mitochondrial form through mitochondrial dynamics are vital for sustaining rod photoreceptor cell health and function. In Aim 1 of this proposal, we will test the hypothesis that mitochondrial fusion is critical for establishing rod photoreceptor cell-specific mitochondrial structures and metabolic status during postnatal development. In Aim 2, we will test the hypothesis that mitofusins maintain the health of rod photoreceptor cells by affecting the metabolic pathways. In Aim 3, we will examine the role of the mitochondrial quality control mechanism through DRP1 in aging rod photoreceptor cells. Successful completion of these studies will provide novel insights into the functional significance of the regulation of mitochondrial dynamics in rod photoreceptor cells, downstream effects of changes in the mitochondrial form, and the link between mitochondrial dynamics dysfunction and neurodegeneration.