[Chinese expert consensus on the clinical diagnosis and treatment of autosomal dominant optic atrophy (2024)].

Autosomal dominant optic atrophy (ADOA) primarily affects retinal ganglion cells and their axons, resulting in varying degrees of central vision loss from childhood. Due to the rarity of ADOA in clinical practice, Chinese ophthalmologists currently lack sufficient understanding of the disease and experience non-standardized diagnostic procedures and high clinical and genetic misdiagnosis rates. To address these issues, the Ophthalmology Group of China Alliance for Rare Diseases/Beijing Society of Rare Disease Clinical Care and Accessibility and the Neuro-ophthalmology Group of Ophthalmology Branch of Chinese Medical Association have established an expert panel to form consensus opinions based on extensive discussions. This consensus would enhance the knowledge and diagnostic capabilities of Chinese clinicians regarding ADOA and promote awareness of related treatment principles and genetic counseling.

Inherited Optic Neuropathies: Real-World Experience in the Paediatric Neuro-Ophthalmology Clinic.

Inherited optic neuropathies affect around 1 in 10,000 people in England; in these conditions, vision is lost as retinal ganglion cells lose function or die (usually due to pathological variants in genes concerned with mitochondrial function). Emerging gene therapies for these conditions have emphasised the importance of early and expedient molecular diagnoses, particularly in the paediatric population. Here, we report our real-world clinical experience of such a population, exploring which children presented with the condition, how they were investigated and the time taken for a molecular diagnosis to be reached. A retrospective case-note review of paediatric inherited optic neuropathy patients (0-16 years) in the tertiary neuro-ophthalmology service at Moorfields Eye Hospital between 2016 and 2020 identified 19 patients. Their mean age was 9.3 ± 4.6 (mean ± SD) years at presentation; 68% were male, and 32% were female; and 26% had comorbidities, with diversity of ethnicity. Most patients had undergone genetic testing (95% (n = 18)), of whom 43% (n = 8) received a molecular diagnosis. On average, this took 54.8 ± 19.5 weeks from presentation. A cerebral MRI was performed in 70% (n = 14) and blood testing in 75% (n = 15) of patients as part of their workup. Continual improvement in the investigative pathways for inherited optic neuropathies will be paramount as novel therapeutics become available.

The human OPA1delTTAG mutation induces adult onset and progressive auditory neuropathy in mice.

Dominant optic atrophy (DOA) is one of the most prevalent forms of hereditary optic neuropathies and is mainly caused by heterozygous variants in OPA1, encoding a mitochondrial dynamin-related large GTPase. The clinical spectrum of DOA has been extended to a wide variety of syndromic presentations, called DOAplus, including deafness as the main secondary symptom associated to vision impairment. To date, the pathophysiological mechanisms underlying the deafness in DOA remain unknown. To gain insights into the process leading to hearing impairment, we have analyzed the Opa1delTTAG mouse model that recapitulates the DOAplus syndrome through complementary approaches combining morpho-physiology, biochemistry, and cellular and molecular biology. We found that Opa1delTTAG mutation leads an adult-onset progressive auditory neuropathy in mice, as attested by the auditory brainstem response threshold shift over time. However, the mutant mice harbored larger otoacoustic emissions in comparison to wild-type littermates, whereas the endocochlear potential, which is a proxy for the functional state of the stria vascularis, was comparable between both genotypes. Ultrastructural examination of the mutant mice revealed a selective loss of sensory inner hair cells, together with a progressive degeneration of the axons and myelin sheaths of the afferent terminals of the spiral ganglion neurons, supporting an auditory neuropathy spectrum disorder (ANSD). Molecular assessment of cochlea demonstrated a reduction of Opa1 mRNA level by greater than 40%, supporting haploinsufficiency as the disease mechanism. In addition, we evidenced an early increase in Sirtuin 3 level and in Beclin1 activity, and subsequently an age-related mtDNA depletion, increased oxidative stress, mitophagy as well as an impaired autophagic flux. Together, these results support a novel role for OPA1 in the maintenance of inner hair cells and auditory neural structures, addressing new challenges for the exploration and treatment of OPA1-linked ANSD in patients.

OPA1 mutation affects autophagy and triggers senescence in autosomal dominant optic atrophy plus fibroblasts.

In several cases of mitochondrial diseases, the underlying genetic and bioenergetic causes of reduced oxidative phosphorylation (OxPhos) in mitochondrial dysfunction are well understood. However, there is still limited knowledge about the specific cellular outcomes and factors involved for each gene and mutation, which contributes to the lack of effective treatments for these disorders. This study focused on fibroblasts from a patient with Autosomal Dominant Optic Atrophy (ADOA) plus syndrome harboring a mutation in the Optic Atrophy 1 (OPA1) gene. By combining functional and transcriptomic approaches, we investigated the mitochondrial function and identified cellular phenotypes associated with the disease. Our findings revealed that fibroblasts with the OPA1 mutation exhibited a disrupted mitochondrial network and function, leading to altered mitochondrial dynamics and reduced autophagic response. Additionally, we observed a premature senescence phenotype in these cells, suggesting a previously unexplored role of the OPA1 gene in inducing senescence in ADOA plus patients. This study provides novel insights into the mechanisms underlying mitochondrial dysfunction in ADOA plus and highlights the potential importance of senescence in disease progression.

Sectorial Ganglion Cell Complex Thickness as Biomarker of Vision Outcome in Patients With Dominant Optic Atrophy.

Purpose: Dominant optic atrophy (DOA) is an inherited condition caused by autosomal dominant mutations involving the OPA-1 gene. The aim of this study was to assess the relationship between macular ganglion cell and inner plexiform layer (GC-IPL) thickness obtained from structural optical coherence tomography (OCT) and visual outcomes in DOA patients. Methods: The study recruited 33 patients with confirmed OPA-1 heterozygous mutation and DOA. OCT scans were conducted to measure the GC-IPL thickness. The average and sectorial Early Treatment Diabetic Retinopathy Study (ETDRS) charts (six-sector macular analysis to enhance the topographical analysis) centered on the fovea were considered. Several regression analyses were carried out to investigate the associations between OCT metrics and final best-corrected visual acuity (BCVA) as the dependent variable. Results: The mean BCVA was 0.43 ± 0.37 logMAR, and the average macular GC-IPL thickness was 43.65 ± 12.56 µm. All of the GC-IPL sectors were significantly reduced and correlated with BCVA. The univariate linear regression and the multivariate stepwise regression modeling showed that the strongest association with final BCVA was observed with the internal superior GC-IPL thickness. Dividing patients based on BCVA, we found a specific pattern. Specifically, in patients with BCVA ≤ 0.3 logMAR, the external superior and inferior sectors together with the internal superior were more significant; whereas, for BCVA > 0.3 logMAR, the external superior sector and internal superior sector were more significant. Conclusions: The study identified OCT biomarkers associated with visual outcomes in DOA patients. Moreover, we assessed a specific OCT biomarker for DOA progression, ranging from patients in the early stages of disease with more preserved GC-IPL sectorial thickness to advanced stages with severe thinning.

A review for the correlation between optic atrophy 1-dependent mitochondrial fusion and cardiovascular disorders.

Mitochondrial dynamics homeostasis is sustained by continuous and balanced fission and fusion, which are determinants of morphology, abundance, biogenesis and mitophagy of mitochondria. Optic atrophy 1 (OPA1), as the only inner mitochondrial membrane fusion protein, plays a key role in stabilizing mitochondrial dynamics. The disturbance of mitochondrial dynamics contributes to the pathophysiological progress of cardiovascular disorders, which are the main cause of death worldwide in recent decades and result in tremendous social burden. In this review, we describe the latest findings regarding OPA1 and its role in mitochondrial fusion. We summarize the post-translational modifications (PTMs) for OPA1 and its regulatory role in mitochondrial dynamics. Then the diverse cell fates caused by OPA1 expression during cardiovascular disorders are discussed. Moreover, cardiovascular disorders (such as heart failure, myocardial ischemia/reperfusion injury, cardiomyopathy and cardiac hypertrophy) relevant to OPA1-dependent mitochondrial dynamics imbalance have been detailed. Finally, we highlight the potential that targeting OPA1 to impact mitochondrial fusion may be used as a novel strategy against cardiovascular disorders.

Human retinal organoids with an OPA1 mutation are defective in retinal ganglion cell differentiation and function.

Autosomal dominant optic atrophy (ADOA), mostly caused by heterozygous OPA1 mutations and characterized by retinal ganglion cell (RGC) loss and optic nerve degeneration, is one of the most common types of inherited optic neuropathies. Previous work using a two-dimensional (2D) differentiation model of induced pluripotent stem cells (iPSCs) has investigated ADOA pathogenesis but failed to agree on the effect of OPA1 mutations on RGC differentiation. Here, we use 3D retinal organoids capable of mimicking in vivo retinal development to resolve the issue. We generated isogenic iPSCs carrying the hotspot OPA1 c.2708_2711delTTAG mutation and found that the mutant variant caused defective initial and terminal differentiation and abnormal electrophysiological properties of organoid-derived RGCs. Moreover, this variant inhibits progenitor proliferation and results in mitochondrial dysfunction. These data demonstrate that retinal organoids coupled with gene editing serve as a powerful tool to definitively identify disease-related phenotypes and provide valuable resources to further investigate ADOA pathogenesis and screen for ADOA therapeutics.

Multi-omics analysis of the oncogenic role of optic atrophy 1 in human cancer.

OBJECTIVE: To investigate the prognostic significance of optic atrophy 1 (OPA1) in pan-cancer and analyze the relationship between OPA1 and immune infiltration in cancer. RESULTS: OPA1 exhibited high expression levels or mutations in various types of tumor cells, and its expression levels were significantly correlated with the survival rate of tumor patients. In different tumor tissues, there was a notable positive correlation between OPA1 expression levels and the infiltration of cancer-associated fibroblasts in the immune microenvironment. Additionally, OPA1 and its related genes were found to be involved in several crucial biological processes, including protein phosphorylation, protein import into the nucleus, and protein binding. CONCLUSION: OPA1 is highly expressed or mutated in numerous tumors and is strongly associated with protein phosphorylation, patient prognosis, and immune cell infiltration. OPA1 holds promise as a novel prognostic marker with potential clinical utility across various tumor types. METHODS: We examined OPA1 expression in pan-cancer at both the gene and protein levels using various databases, including Tumor Immune Estimation Resource 2.0 (TIMER 2.0), Gene Expression Profiling Interactive Analysis (GEPIA2), UALCAN, and The Human Protein Atlas (HPA). We utilized the Kaplan-Meier plotter and GEPIA datasets to analyze the relationship between OPA1 expression levels and patient prognosis. Through the cBioPortal database, we detected OPA1 mutations in tumors and examined their relationship with patient prognosis. We employed the TIMER 2.0 database to explore the correlation between OPA1 expression levels in tumor tissue and the infiltration of cancer-associated fibroblasts in the immune microenvironment. Furthermore, we conducted a gene search associated with OPA1 and performed enrichment analysis to identify the main signaling pathways and biological processes linked to them.

Mitochondrial OPA1 Deficiency Is Associated to Reversible Defects in Spatial Memory Related to Adult Neurogenesis in Mice.

Mitochondria are integrative hubs central to cellular adaptive pathways. Such pathways are critical in highly differentiated postmitotic neurons, the plasticity of which sustains brain function. Consequently, defects in mitochondria and in their dynamics appear instrumental in neurodegenerative diseases and may also participate in cognitive impairments. To directly test this hypothesis, we analyzed cognitive performances in a mouse mitochondria-based disease model, because of haploinsufficiency in the mitochondrial optic atrophy type 1 (OPA1) protein involved in mitochondrial dynamics. In males, we evaluated adult hippocampal neurogenesis parameters using immunohistochemistry. We performed a battery of tests to assess basal behavioral characteristics and cognitive performances, and tested putative treatments. While in dominant optic atrophy (DOA) mouse models, the known main symptoms are late onset visual deficits, we discovered early impairments in hippocampus-dependent spatial memory attributable to defects in adult neurogenesis. Moreover, less connected adult-born hippocampal neurons showed a decrease in mitochondrial content. Remarkably, voluntary exercise or pharmacological treatment targeting mitochondrial dynamics restored spatial memory in DOA mice. Altogether, our study identifies a crucial role for OPA1-dependent mitochondrial functions in adult neurogenesis, and thus in hippocampal-dependent cognitive functions. More generally, our findings show that adult neurogenesis is highly sensitive to mild mitochondrial defects, generating impairments in spatial memory that can be detected at an early stage and counterbalanced by physical exercise and pharmacological targeting of mitochondrial dynamics. Thus, amplification of mitochondrial function at an early stage appears beneficial for late-onset neurodegenerative diseases.

[Long noncoding RNA H19 promotes vascular calcification by repressing the Bax inhibitor 1/optic atrophy 1 pathway].

OBJECTIVE: To investigate whether long noncoding RNA H19 (lncRNA H19) induces vascular calcification by promoting calcium deposition, osteogenic differentiation and apoptosis via inhibiting the Bax inhibitor 1/optic atrophy 1 (BI-1/ OPA1) pathway. METHODS: ß-glycerophosphate and calcium chloride were used to induce calcification in rat vascular smooth muscle cells (VSMCs), and the effects of siH19, alone or in combination with BI-1 or OPA1 knockdown, on calcification of the cells were investigated. Osteogenic differentiation was assessed by measuring Runt-related transcription factor 2 (Runx-2) and bone morphogenetic protein 2 (BMP-2) expression with Western blotting, and cell apoptosis was evaluated by TUNEL staining and Western blotting. An ApoE-/- diabetic mouse model with high-fat feeding for 32 weeks were given an intraperitoneal injection of siH19, and the changes in calcium deposition in the aortic arch were examined using Alizarin red S staining and von Kossa staining. RESULTS: In rat VSMCs with calcification, the expression of lncRNA H19 was significantly increased, and the expressions of BI- 1 and OPA1 were significantly decreased. Downregulation of lncRNA H19 significantly increased the expressions of BI-1 and OPA1 proteins in the cells, and BI-1 knockdown further reduced OPA1 expression (P<0.001). The cells treated with siH19 showed total disappearance of the calcified nodules with significantly reduced expressions of Runx-2, BMP-2 and cleaved caspase-3 and a lowered cell apoptosis rate (P<0.001). Calcified nodules were again observed in the cells with lncRNA H19 knockdown combined with BI-1 or OPA1 knockdown, and the expressions of Runx-2, BMP-2, cleaved-caspase-3 and cell apoptosis rate all significantly increased (P<0.001). In the diabetic mouse model with high-fat feeding, siH19 treatment significantly reduced the calcification area and increased mRNA expressions of BI-I and OPA1 in the aortic arch. CONCLUSION: LncRNA H19 promotes vascular calcification possibly by promoting calcium deposition, osteogenic differentiation and cell apoptosis via inhibiting the BI-1/OPA1 pathway.

OPA1 deficiency impairs oxidative metabolism in cycling cells, underlining a translational approach for degenerative diseases.

Dominant optic atrophy is an optic neuropathy with varying clinical symptoms and progression. A severe disorder is associated with certain OPA1 mutations and includes additional symptoms for >20% of patients. This underscores the consequences of OPA1 mutations in different cellular populations, not only retinal ganglionic cells. We assessed the effects of OPA1 loss of function on oxidative metabolism and antioxidant defences using an RNA-silencing strategy in a human epithelial cell line. We observed a decrease in the mitochondrial respiratory chain complexes, associated with a reduction in aconitase activity related to an increase in reactive oxygen species (ROS) production. In response, the NRF2 (also known as NFE2L2) transcription factor was translocated into the nucleus and upregulated SOD1 and GSTP1. This study highlights the effects of OPA1 deficiency on oxidative metabolism in replicative cells, as already shown in neurons. It underlines a translational process to use cycling cells to circumvent and describe oxidative metabolism. Moreover, it paves the way to predict the evolution of dominant optic atrophy using mathematical models that consider mitochondrial ROS production and their detoxifying pathways.

Visual Function and Inner Retinal Structure in Relation to Birth Factors in Autosomal Dominant Optic Atrophy.

Purpose: The extreme variation in expressivity of autosomal dominant optic atrophy (ADOA) is unexplained. It is present from early childhood, why there is reason to search for pre- and perinatal risk factors for poor vision in ADOA. The process of ganglion cell pruning in the fetus is of interest because mitochondria are involved in apoptosis. We hypothesized that suboptimal mitochondrial function makes the developing retina and optic nerve vulnerable to fetal stress in ADOA. We have examined visual function and inner retinal layer structure in relation to birth parameters in ADOA. Methods: The study included 142 participants with OPA1 ADOA, 62 unaffected first-degree relatives, and 90 unrelated control subjects. Outcome measures included best-corrected visual acuity, microperimetric sensitivity, nerve fiber layer (NFL) volume, and ganglion cell layer (GCL) volume. Descriptive parameters included birth weight, maternal age at birth, birth complications, and gestational age. Analysis was made using mixed modeling. Results: The analysis showed a significant positive association between microperimetric sensitivity and longer gestational age in ADOA (0.5 dB/week, P = 0.017). Interaction analysis showed a significant different association between microperimetric sensitivity and gestational age between participants with ADOA and the control groups (P = 0.007) and a significant difference in association between NFL volume and birth weight (P = 0.04) and gestational age (P = 0.02) between variant types. Conclusions: The study suggests that gestational age and birth weight may affect the expressivity of ADOA. The results support that prospectively collected pre- and perinatal data should be included in future studies of the natural history of ADOA.

Oxidization of optic atrophy 1 cysteines occurs during heart ischemia-reperfusion and amplifies cell death by oxidative stress.

During cardiac ischemia-reperfusion, excess reactive oxygen species can damage mitochondrial, cellular and organ function. Here we show that cysteine oxidation of the mitochondrial protein Opa1 contributes to mitochondrial damage and cell death caused by oxidative stress. Oxy-proteomics of ischemic-reperfused hearts reveal oxidation of the C-terminal C786 of Opa1 and treatment of perfused mouse hearts, adult cardiomyocytes, and fibroblasts with H2O2 leads to the formation of a reduction-sensitive ∼180 KDa Opa1 complex, distinct from the ∼270 KDa one antagonizing cristae remodeling. This Opa1 oxidation process is curtailed by mutation of C786 and of the other 3 Cys residues of its C-terminal domain (Opa1TetraCys). When reintroduced in Opa1-/- cells, Opa1TetraCys is not efficiently processed into short Opa1TetraCys and hence fails to fuse mitochondria. Unexpectedly, Opa1TetraCys restores mitochondrial ultrastructure in Opa1-/- cells and protects them from H2O2-induced mitochondrial depolarization, cristae remodeling, cytochrome c release and cell death. Thus, preventing the Opa1 oxidation occurring during cardiac ischemia-reperfusion reduces mitochondrial damage and cell death induced by oxidative stress independent of mitochondrial fusion.

Ginsenoside Rg1 protects cardiac mitochondrial function via targeting GSTP1 to block S-glutathionylation of optic atrophy 1.

Mitochondrial dysfunction is a fundamental challenge in myocardial injury. Ginsenoside Rg1 (Rg1) is a bioactive compound with pharmacological potential for cardiac protection. Optic atrophy 1 (OPA1) acts as a mitochondrial inner membrane protein that contributes to the structural integrity and function of mitochondria. This study investigated the protective role of Rg1 in septic cardiac injury from the perspective of OPA1 stability. Rg1 protected cardiac contractive function against endotoxin injury in mice by maintaining mitochondrial cristae structure. In cardiomyocytes, lipopolysaccharide (LPS) evoked mitochondrial fragmentation and destruction of mitochondrial biogenesis, which were prevented by Rg1, possibly due to the preservation of the integrity of cristae structure. In support, the beneficial effects of Rg1 on cardioprotection and mitochondrial biogenesis were diminished by OPA1 deficiency subjected to the LPS challenge. Mechanistically, LPS stimulation triggered intracellular glutathione destabilization that promoted S-glutathionylation of OPA1 at Cys551, leading to the dissociation of OPA1-Mitofilin. Rg1 interacted with Glutathione S-transferase pi (GSTP1) to inhibit its mediated S-glutathionylation of OPA1, thereby promoting OPA1-Mitofilin interaction and protecting mitochondrial cristae structure. These findings suggest that GSTP1/OPA1 axis may be a beneficial strategy for the treatment of myocardial injury, and expand the clinical application of Rg1.

OPA1 disease-causing mutants have domain-specific effects on mitochondrial ultrastructure and fusion.

Inner mitochondrial membrane fusion and cristae shape depend on optic atrophy protein 1, OPA1. Mutations in OPA1 lead to autosomal dominant optic atrophy (ADOA), an important cause of inherited blindness. The Guanosin Triphosphatase (GTPase) and GTPase effector domains (GEDs) of OPA1 are essential for mitochondrial fusion; yet, their specific roles remain elusive. Intriguingly, patients carrying OPA1 GTPase mutations have a higher risk of developing more severe multisystemic symptoms in addition to optic atrophy, suggesting pathogenic contributions for the GTPase and GED domains, respectively. We studied OPA1 GTPase and GED mutations to understand their domain-specific contribution to protein function by analyzing patient-derived cells and gain-of-function paradigms. Mitochondria from OPA1 GTPase (c.870+5G>A and c.889C>T) and GED (c.2713C>T and c.2818+5G>A) mutants display distinct aberrant cristae ultrastructure. While all OPA1 mutants inhibited mitochondrial fusion, some GTPase mutants resulted in elongated mitochondria, suggesting fission inhibition. We show that the GED is dispensable for fusion and OPA1 oligomer formation but necessary for GTPase activity. Finally, splicing defect mutants displayed a posttranslational haploinsufficiency-like phenotype but retained domain-specific dysfunctions. Thus, OPA1 domain-specific mutants result in distinct impairments in mitochondrial dynamics, providing insight into OPA1 function and its contribution to ADOA pathogenesis and severity.

Choroidal vascularity index in hereditary optic neuropathies.

PURPOSE: To assess the choroidal vascularity index (CVI) in patients affected by Leber hereditary optic neuropathy (LHON) compared to patients affected by dominant optic atrophy (DOA) and healthy subjects. METHODS: In this retrospective study, we considered three cohorts: LHON eyes (48), DOA eyes (48) and healthy subjects' eyes (48). All patients underwent a complete ophthalmologic examination, including best-corrected visual acuity (BCVA) and optical coherence tomography (OCT) acquisition. OCT parameters as subfoveal choroidal thickness (Sub-F ChT), mean choroidal thickness (ChT), total choroidal area (TCA), luminal choroidal area (LCA) were calculated. CVI was obtained as the ratio of LCA and TCA. RESULTS: Subfoveal ChT in LHON patients did not show statistically significant differences compared to controls, while in DOA a reduction in choroidal thickness was observed (p = 0.344 and p = 0.045, respectively). Mean ChT was reduced in both LHON and DOA subjects, although this difference reached statistical significance only in DOA (p = 0.365 and p = 0.044, respectively). TCA showed no significant differences among the 3 cohorts (p = 0.832). No changes were detected in LCA among the cohorts (p = 0.389), as well as in the stromal choroidal area (SCA, p = 0.279). The CVI showed no differences among groups (p = 0.898): LHON group was characterized by a similar CVI in comparison to controls (p = 0.911) and DOA group (p = 0.818); the DOA group was characterized by a similar CVI in comparison to controls (p = 1.0). CONCLUSION: CVI is preserved in DOA and LHON patients, suggesting that even in the chronic phase of the neuropathy the choroidal structure is not irreversibly compromised.

Mitochondrial optic neuropathies.

Mitochondrial optic neuropathies have a leading role in the field of mitochondrial medicine ever since 1988, when the first mutation in mitochondrial DNA was associated with Leber's hereditary optic neuropathy (LHON). Autosomal dominant optic atrophy (DOA) was subsequently associated in 2000 with mutations in the nuclear DNA affecting the OPA1 gene. LHON and DOA are both characterized by selective neurodegeneration of retinal ganglion cells (RGCs) triggered by mitochondrial dysfunction. This is centered on respiratory complex I impairment in LHON and defective mitochondrial dynamics in OPA1-related DOA, leading to distinct clinical phenotypes. LHON is a subacute, rapid, severe loss of central vision involving both eyes within weeks or months, with age of onset between 15 and 35 years old. DOA is a more slowly progressive optic neuropathy, usually apparent in early childhood. LHON is characterized by marked incomplete penetrance and a clear male predilection. The introduction of next-generation sequencing has greatly expanded the genetic causes for other rare forms of mitochondrial optic neuropathies, including recessive and X-linked, further emphasizing the exquisite sensitivity of RGCs to compromised mitochondrial function. All forms of mitochondrial optic neuropathies, including LHON and DOA, can manifest either as pure optic atrophy or as a more severe multisystemic syndrome. Mitochondrial optic neuropathies are currently at the forefront of a number of therapeutic programs, including gene therapy, with idebenone being the only approved drug for a mitochondrial disorder.

The effects of nuclear DNA mutations on mitochondrial function.

ABSTRACT: The multiple functions of mitochondria, including adenosine triphosphate synthesis, are controlled by the coordination of both the mitochondrial DNA (mtDNA) and the nuclear DNA (nDNA) genomes. Mitochondrial disorders manifest because of impairment of energy metabolism. This article focuses on mutations in two nuclear genes and their effect on mitochondrial function. Mutations in the polymerase gamma, or POLG, gene are associated with multisystemic disease processes, including Alpers Syndrome, a severe childhood-onset syndrome. Mutations in the OPA1 gene are associated with autosomal dominant optic atrophy and other neurologic, musculoskeletal, and ophthalmologic symptoms. When assessing for disorders affecting energy metabolism, sequencing of both the mtDNA genome and the nDNA whole exome sequencing is necessary.