Opa1 deficiency leads to diminished mitochondrial bioenergetics with compensatory increased mitochondrial motility
Autor: | Shanshan Sun, Frank Sengpiel, Irina Erchova, Marcela Votruba |
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Jazyk: | angličtina |
Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Retinal Ganglion Cells Cell type mitochondrial motility endocrine system Bioenergetics Neurite genetic structures Blotting Western Motility Mitochondrion Retinal ganglion OPA1 GTP Phosphohydrolases mitochondrial bioenergetics 03 medical and health sciences Mice 0302 clinical medicine Optic Atrophy Autosomal Dominant Extracellular medicine autosomal dominant optic atrophy Animals Cells Cultured Chemistry Biochemistry and Molecular Biology General Medicine Adenosine eye diseases Cell biology Mitochondria Mice Inbred C57BL Disease Models Animal 030104 developmental biology Mutation sense organs Energy Metabolism 030217 neurology & neurosurgery medicine.drug |
Zdroj: | Investigative Ophthalmology & Visual Science |
ISSN: | 0146-0404 |
Popis: | Purpose: Retinal ganglion cells (RGCs) are susceptible to mitochondrial deficits and also the major cell type affected in patients with mutations in the OPA1 gene in autosomal dominant optic atrophy (ADOA). Here, we characterized mitochondria in RGCs in vitro from a heterozygous B6; C3-Opa1Q285STOP (Opa1+/−) mouse model to investigate mitochondrial changes underlying the pathology in ADOA.\ud\udMethods: Mouse RGCs were purified from wild-type and Opa1+/− mouse retina by two-step immunopanning. The mitochondria in neurites of RGCs were labeled with MitoTracker Red for structure and motility measurement by time-lapse imaging. Mitochondrial bioenergetics were determined by the real-time measurement of oxygen consumption rate using a Seahorse XFe 96 Extracellular Flux Analyzer.\ud\udResults: We observed a significant decrease in mitochondrial length in Opa1+/− RGCs with a remarkably higher proportion and density of motile mitochondria along the neurites. We also observed an increased transport velocity with a higher number of contacts between mitochondria in Opa1+/− RGC neurites. The oxygen consumption assays showed a severe impairment in basal respiration, Adenosine triphosphate-linked (ATP-linked) oxygen consumption, as well as reserve respiratory capacity, in RGCs from Opa1+/− mouse retina.\ud\udConclusions: Opa1 deficiency leads to significant fragmentation of mitochondrial morphology, activation of mitochondrial motility and impaired respiratory function in RGCs from the B6; C3-Opa1Q285STOP mouse model. This highlights the significant alterations in the intricate interplay between mitochondrial morphology, motility, and energy production in RGCs with Opa1 deficiency long before the onset of clinical symptoms of the pathology. |
Databáze: | OpenAIRE |
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