Sirtuin 3 mutation- induced mitochondrial dysfunction and optic neuropathy: a case report

Abstract

Background

Mitochondrial optic neuropathy is characterized by painless, progressive, symmetrical central vision loss, and dyschromatopsia owing to mitochondrial dysfunction. This report documents a rare case of mitochondrial optic neuropathy due to the SIRT3 gene mutation.

Case presentation

This report describes a case of a 17-year-old boy who presented with symptoms of bilateral painless, progressive vision decline over several years. Fundus examination revealed temporal pallor of the optic nerve head in both the eyes and an OCT showed considerable thinning of the retinal nerve fiber and ganglion cell layers. Pathogenicity was confirmed by decreased mitochondrial function measured by bioenergetic health index and oxygen consumption rate in this patient. Subsequent NGS revealed a missense mutation of the SIRT3 gene (c.1137G > C, p.Trp379Cys) in the patient.

Conclusions

This case describes the clinical manifestation of mitochondrial optic neuropathy due to the SIRT3 gene mutation.

Background

Mitochondria produce energy through oxidative phosphorylation and are indispensable in the life of cells, especially neurons [1]. Since the visual system’s function relies mainly on the mitochondrial energy supply, the eye is one of the organs with the densest mitochondrial population in the body [1]. Retinal ganglion cells (RGCs) and their axons are preferentially vulnerable to neurodegeneration due to mitochondrial dysfunction [1]. Mitochondrial optic neuropathy is characterized by painless, progressive, symmetrical central vision loss, and dyschromatopsia owing to mitochondrial dysfunction. Leber’s hereditary optic neuropathy and dominant optic atrophy (DOA) are the two most common inherited optic neuropathies related to mitochondrial dysfunction observed in clinical practice [2]. However, mutations of any genes, which affect mitochondrial function, can theoretically induce mitochondrial optic neuropathy. Here, we present a rare case of mitochondrial optic neuropathy from a missense mutation of the sirtuin 3 (SIRT3) gene.

Case presentation

A 17-year-old boy presented with a primary complaint of bilateral painless, progressive vision decline over several years. Except for dyschromatopsia, his past medical, ocular, and neurological symptoms were unremarkable. There was no history of trauma or medication intake, and he did not smoke or drink. His father and sister were healthy and had no vision-related problems. However, his mother seemed to have mild mental retardation. The best-corrected visual acuity (BCVA) in both eyes of the patients was 20/80, without any relative afferent pupillary defect. He was orthophoric and demonstrated full duction and version. He identified three Ishihara color plates with each eye. The findings of the slit lamp examination, including measurement of the intraocular pressure were normal; however, fundus examination revealed temporal pallor of the optic nerve head in both eyes (Fig. 1). The Goldmann visual field test demonstrated cecocentral scotomas in both the eyes, and optical coherence tomography (OCT) showed considerable thinning of the peripapillary retinal nerve fiber layer (RNFL) and macular ganglion cell layers, which demonstrated preferential loss of the the papillomacular bundle in both eyes (Fig. 2). However, the electrophysiology retinogram revealed normal. Orbital magnetic resonance imaging with gadolinium enhancement demonstrated no abnormal findings. Genetic testing by whole genome sequencing of the mitochondrial DNA was normal. However, next-generation sequencing of the optic atrophy panel revealed a missense mutation of the SIRT3 gene (c.1137G > C, p.Trp379Cys) in the patient and his mother. BCVA of his mother was 20/32 in both eyes without any relative afferent pupillary defect. She identified six Ishhara color plate with each eye. Her fundus examination revealed temporal pallor of the optic nerve head in both eyes, and OCT revealed thinning of the peripapillary RNFL and macular ganglion cell layers of both eyes (Fig. 3). The Goldmann visual field test was not available due to her poor cooperation.

Fig. 1

Fundus photography of the patient. Fundus examination showed temporal pallor of the optic nerve head in both eyes

Fig. 2

Optical coherence tomography of the patient. It showed considerable thinning of the peripapillary retinal nerve fiber layer and macular ganglion cell layers, which demonstrated preferential loss of the the papillomacular bundle in both eyes

Fig. 3

Fundus photography and Optical coherence tomogtaphy of the patient’s mother. Fundus examination showed temporal pallor of the optic nerve head in both eyes. Optical coherence tomography showed considerable thinning of the peripapillary retinal nerve fiber layer and macular ganglion cell layers in both eyes

Mitochondrial function measurement in the patient’s peripheral blood mononuclear cells with the Seahorse XF Cell Mito Stress Test kit (Agilent, Santa Clara, USA) revealed a significant decrease in the function measured as a bioenergetic health index (BHI) and oxygen consumption rate (OCR) compared with those of age and sex matched healthy control (Fig. 4). Two years after the initial presentation, the BCVA in both eyes decreased to 20/100 and 20/125 each, and he demonstrated temporal optic nerve head pallor and stabilized RNFL thinning on OCT.

Fig. 4

Mitochondrial function measurement in the patient’s peripheral blood mononuclear cells with the Seahorse XF Cell Mito Stress Test kit (Agilent, Santa Clara, USA) revealed a significant decrease in the function measured as a bioenergetic health index (BHI) and oxygen consumption rate (OCR) compared with those of age and sex matched healthy control

Discussion and conclusions

Sirtuins are a family of seven proteins with nicotinamide adenine dinucleotide-dependent deacetylase activity that regulate multiple cellular processes, such as stress resistance, apoptosis, inflammation, and mitochondrial energy homeostasis [3]. In mammals, SIRT3, 4, and 5 are localized in the mitochondrial matrix and modulate mitochondrial metabolism, but it is the SIRT3 that functions uniquely as a major regulator of the whole organelle acetylome [3]. It is a key modulator in maintaining mitochondrial integrity and functions by regulating the metabolic enzyme activity and mitochondrial fusion by activation of the optic atrophy 1 (OPA1) [3, 4]. OPA1, reported as a direct target of SIRT3, is hyperacetylated, and its GTPase activity diminishes under stress conditions [3, 4]. SIRT3 deacetylates and activates OPA1 and fine-tunes mitochondrial dynamics during cellular stress [3, 4]. SIRT3 silencing can lead to hyperacetylation of mitochondrial proteins and mitochondrial dysfunction [3, 4]. Therefore, SIRT3 is recognized as the major mitochondrial deacetylase.

DOA is the most commonly diagnosed hereditary optic atrophy, causing progressive bilateral vision loss which begins early in life [1, 2]. The OPA1 gene is the most common gene mutated in DOA and accounts for 65–90% of all cases of DOA [1, 2]. Recently, Rocatcher et al. [5] reported the top 10 most frequently involved genes in hereditary optic neuropathies; the OPA1 gene was the first position in the top 10 nuclear genes, followed by WFS1, ACO2, SPG7, MFN2, AFG3L2, RTN4IP1, TMEM126A, NR2F1 and FDXR. Their results revealed that those 10 genes accounted for 96% of the cases of hereditary optic neuropathies, and the majority of the implicated genes directly linked to mitochondrial function [5]. A study on the application of next-generation sequencing in suspected hereditary optic atrophy in Korean also supports the OPA1 variants as being the major genetic causes [6]. They reported that the OPA1 variants were found to be the major causes of hereditary optic atrophy, accounting for 38.9% of their cases [6].

Our patient presented with typical manifestations of DOA, i.e., progressive, symmetrical, painless, bilateral vision loss, and dyschromatopsia. Examinations revealed the temporal pallor of the optic nerve head and selective thinning of the peripapillary RNFL and macular ganglion cell layers. Loss of OPA1 protein function by OPA1 gene mutations leads to mitochondrial dysfunction that eventually causes apoptosis of the RGCs in patients with DOA [2]. Therefore, we clinically diagnosed the patient with DOA and hypothesized that he might have mutations in the OPA1 gene or OPA1 interacting proteins. Although he presented with typical ophthalmologic manifestations of mitochondrial optic neuropathy, his mother presented with a relatively better vision than his son, despite having identical SIRT3 mutation. This difference in clinical severity might be explained by sex-specific susceptibility to visual defects due to mitochondrial dysfunction [7]. Molecular diagnosis was achieved by next-generation sequencing but suspected based on the clinical phenotype. Pathogenicity was confirmed by decreased mitochondrial function measured by BHI and OCR in this patient. This finding corresponds with a previous study that reported that reduced basal OCR was observed in skeletal muscles of the SIRT3 knockout mice [4]. Recent findings show that SIRT3 activity is vital to the expression levels of OPA1, and SIRT3 can directly interact with and deacetylate OPA1 [3, 4]. SIRT3- induced OPA1 deacetylation can increase its GTPase activity to promote the fusion of the inner mitochondrial membrane and maintain mitochondrial dynamics [3, 4].

Consistent with these reports, our case suggests that SIRT3 mutation can induce mitochondrial optic neuropathy caused by mitochondrial dysfunction. To the best of our knowledge, this is the first report of mitochondrial optic neuropathy from the missense mutation of the SIRT3 gene. This case report emphasizes that not only mutations of OPA1 gene but also OPA1 interacting proteins may cause mitochondrial optic neuropathy.