Opa1 deficiency leads to diminished mitochondrial bioenergetics with compensatory increased mitochondrial motility

Sun, Shanshan, Erchova, Irina, Sengpiel, Frank ORCID: https://orcid.org/0000-0002-7060-1851 and Votruba, Marcela ORCID: https://orcid.org/0000-0002-7680-9135 2020. Opa1 deficiency leads to diminished mitochondrial bioenergetics with compensatory increased mitochondrial motility. Investigative Ophthalmology & Visual Science 61 (6) , 42. 10.1167/iovs.61.6.42

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Abstract

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. Methods: 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. Results: 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. Conclusions: 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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Optometry and Vision Sciences Biosciences
Publisher:	Association for Research in Vision and Ophthalmology
ISSN:	0146-0404
Date of First Compliant Deposit:	29 June 2020
Date of Acceptance:	20 May 2020
Last Modified:	23 May 2023 07:57
URI:	https://orca.cardiff.ac.uk/id/eprint/132869

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