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Exploring mito-nuclear genetic factors in Leber's hereditary optic neuropathy: insights from comprehensive profiling of unique cases.

ABSTRACT: Leber's hereditary optic neuropathy (LHON) is a mitochondrial complex I disorder and causes inexorable painless vision loss. Recent studies from India reported that a significant proportion of LHON patients lack primary mitochondrial DNA mutations, suggesting that alternative genetic factors contribute to disease development. Therefore, this study investigated the genetic profile of LHON-affected individuals in order to understand the role of mito-nuclear genetic factors in LHON. A total of thirty probands displaying symptoms consistent with LHON have undergone whole mitochondrial and whole exome sequencing. Interestingly, whole mtDNA sequencing revealed primary mtDNA mutations in 30 % of the probands (n=9), secondary mtDNA mutations in 40 % of the probands (n=12) and no mitochondrial changes in 30 % of individuals (n=9). Further, WES analysis determined pathogenic mutations in 11 different nuclear genes, especially in cases with secondary mtDNA mutations (n=6) or no mtDNA mutations (n=6). These findings provide valuable insight into LHON genetic predisposition, particularly in cases lacking primary mtDNA mutations. See also Figure 1(Fig. 1).

SUBMITTER: Chermakani P

PROVIDER: S-EPMC10694345 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Exploring mito-nuclear genetic factors in Leber's hereditary optic neuropathy: insights from comprehensive profiling of unique cases.

Chermakani Prakash P Gowri Poigaialwar P Mahesh Kumar Shanmugam S Sundaresan Periasamy P

EXCLI journal 20231009

Leber's hereditary optic neuropathy (LHON) is a mitochondrial complex I disorder and causes inexorable painless vision loss. Recent studies from India reported that a significant proportion of LHON patients lack primary mitochondrial DNA mutations, suggesting that alternative genetic factors contribute to disease development. Therefore, this study investigated the genetic profile of LHON-affected individuals in order to understand the role of mito-nuclear genetic factors in LHON. A total of thir ...[more]

PMID: 38054206

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Project description:PurposeTo screen mitochondrial DNA (mtDNA) variations in Leber hereditary optic neuropathy (LHON).MethodsTen LHON patients were selected from neuro-ophthalmology clinics of All India Institute of Medical Sciences (AIIMS), New Delhi, India. Clinical evaluation included slit-lamp biomicroscopy, fundus examination, and neuroimaging. DNA was isolated from whole blood samples. The entire coding region of the mitochondrial genome was amplified by PCR in ten patients and 20 controls. The full mtDNA genome except D-loop was sequenced. All sequences were analyzed against mitochondrial reference sequence NC_012920.ResultsMtDNA sequencing revealed a total of 30 nucleotide variations in the ten LHON patients and 29 in the 20 controls. Of 30 changes, 30.00% (9/30) were nonsynonymous, and the remaining 70.00% (21/30) were synonymous. In controls, a total of five changes were nonsynonymous. Out of the total 14 nonsynonymous changes observed in cases and controls, four (p.A52T in nicotinamide adenine dinucleotide [NADH] dehydrogenase [ND1] protein; p.L128Q in ND2; p.W48R in ATPase6; p.R340H in ND4 protein) were pathogenic. Four patients were positive for either of pathogenic changes. In total, 16.66% (5/30) variations were novel out of which 40.00% (2/5) were nonsynonymous. All novel variations were submitted to the GenBank database, and accession numbers were obtained. Primary LHON mutations in complex I genes have been considered a hallmark feature of LHON patients, and primary LHON mutations were present in two cases in this study. Mutations in complex I genes (ND genes) account for 50%-90% of LHON pedigrees in different ethnic pedigrees. In this study the highest numbers of changes were also present in complex I genes (46.66%; 14/30) followed by complex IV (30.00%; 9/30), complex III (16.66%; 5/30), and then complex V (6.66%; 2/30). Complex I had 5/30 (16.66%) nonsynonymous changes, complex III had 1/30 (3.33%), complex IV had 1/30 (3.33%), and complex V had 2/30 (6.66%) nonsynonymous changes. Nonsynonymous mutations in cytochrome c oxidase (COX) genes have been reported previously in LHON patients. Nonsynonymous mtDNA variations may adversely affect the respiratory chain and impair the oxidative phosphorylation (OXPHOS) pathway, resulting in low ATP production and elevated reactive oxygen species (ROS) levels, which cause oxidative stress. It has previously been reported that oxidative stress (OS) leads to oxidative damage of cellular macromolecules, such as mitochondrial and nuclear DNA, proteins, and lipids along with energy depletion and a local imbalance of calcium homeostasis, resulting in neuronal degeneration. OS is the underlying etiology in several ocular diseases and also plays an essential role in LHON.ConclusionsA total of five novel mtDNA variations were identified in this study. Nonsynonymous mtDNA variations may adversely affect the respiratory chain and impair the OXPHOS pathway, resulting in low ATP production and elevated ROS levels. OS further damages both nuclear and mtDNA. This preliminary study describes mtDNA sequence variations in a relatively small number of LHON patients of north Indian ethnic origin. However, these results should be confirmed in other populations. Early diagnosis of mtDNA variations and prompt anti-oxidant administration in these cases may delay OS-induced injury to retinal ganglion cells (RGCs) and hence improve visual prognosis.

Project description:Leber's hereditary optic neuropathy (LHON, MIM#535000) is the most common form of inherited optic neuropathies and mitochondrial DNA-related diseases. The pathogenicity of mutations in genes encoding components of mitochondrial Complex I is well established, but the underlying pathomechanisms of the disease are still unclear. Hypothesizing that oxidative stress related to Complex I deficiency may increase protein S-glutathionylation, we investigated the proteome-wide S-glutathionylation profiles in LHON (n = 11) and control (n = 7) fibroblasts, using the GluICAT platform that we recently developed. Glutathionylation was also studied in healthy fibroblasts (n = 6) after experimental Complex I inhibition. The significantly increased reactive oxygen species (ROS) production in the LHON group by Complex I was shown experimentally. Among the 540 proteins which were globally identified as glutathionylated, 79 showed a significantly increased glutathionylation (p < 0.05) in LHON and 94 in Complex I-inhibited fibroblasts. Approximately 42% (33/79) of the altered proteins were shared by the two groups, suggesting that Complex I deficiency was the main cause of increased glutathionylation. Among the 79 affected proteins in LHON fibroblasts, 23% (18/79) were involved in energetic metabolism, 31% (24/79) exhibited catalytic activity, 73% (58/79) showed various non-mitochondrial localizations, and 38% (30/79) affected the cell protein quality control. Integrated proteo-metabolomic analysis using our previous metabolomic study of LHON fibroblasts also revealed similar alterations of protein metabolism and, in particular, of aminoacyl-tRNA synthetases. S-glutathionylation is mainly known to be responsible for protein loss of function, and molecular dynamics simulations and 3D structure predictions confirmed such deleterious impacts on adenine nucleotide translocator 2 (ANT2), by weakening its affinity to ATP/ADP. Our study reveals a broad impact throughout the cell of Complex I-related LHON pathogenesis, involving a generalized protein stress response, and provides a therapeutic rationale for targeting S-glutathionylation by antioxidative strategies.

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Exploring mito-nuclear genetic factors in Leber's hereditary optic neuropathy: insights from comprehensive profiling of unique cases.

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Exploring mito-nuclear genetic factors in Leber's hereditary optic neuropathy: insights from comprehensive profiling of unique cases.

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