Isolation of transcriptomal changes attributable to LHON mutations and the cybridization process

Danielson, Steven R.; Carelli, Valerio; Tan, Guolin; Martinuzzi, Andrea; Schapira, Anthony H. V.; Savontaus, Marja-Liisa; Cortopassi, Gino A.

doi:10.1093/brain/awh447

Cited by 48Mitochondrial Function and PathologyAldose Reductase and TaurineGlaucoma and retinal disorders

Isolation of transcriptomal changes attributable to LHON mutations and the cybridization process

Danielson, Steven R., Carelli, Valerio, Tan, Guolin, Martinuzzi, Andrea, Schapira, Anthony H. V., Savontaus, Marja-Liisa, Cortopassi, Gino A.·2005·Brain

DOI 10.1093/brain/awh447

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Abstract

Leber's hereditary optic neuropathy (LHON) is thought to be the most common disease resulting from mitochondrial DNA (mtDNA) point mutations, and transmitochondrial cytoplasmic hybrid (cybrid) cell lines are the most frequently used model for understanding the pathogenesis of mitochondrial disorders. We have used oligonucleotide microarrays and a novel study design based on shared transcripts to allocate transcriptomal changes into rho-zero-dependent, cybridization-dependent and LHON-dependent categories in these cells. The analysis indicates that the rho-zero process has the largest transcriptomal impact, followed by the cybridization process, and finally the LHON mutations. The transcriptomal impacts of the rho-zero and cybridization processes preferentially and significantly affect the mitochondrial compartment, causing upregulation of many transcripts involved in oxidative phosphorylation, presumably in response to the mtDNA depletion that occurs at the rho-zero step. Nine LHON-specific transcriptional alterations were shared among osteosarcoma cybrids and lymphoblasts bearing LHON mutations. Notably, the aldose reductase transcript was overexpressed in LHON cybrids and lymphoblasts. Aldose reductase is also overexpressed in diabetic retinopathy, leading to optic nerve and retinal complications. The LHON-specific increase in transcript level was confirmed by quantitative reverse transcription-polymerase chain reaction (RT-PCR), and a western blot confirmed a higher level of aldose reductase in mutant mitochondria. One product of aldose reductase is sorbitol, which has been linked to osmotic stress, oxidative stress and optic neuropathy, and sorbitol levels were increased in LHON cybrids. If these results are confirmed in patient tissues, aldose reductase inhibitors could have some therapeutic value for LHON.

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Both ρ0 and cybridisation processes can cause significant and stable up-regulation of many nuclear transcripts involved in OXPHOS, even after repopulation of ρ0 cells with wild-type mitochondria.
“Indeed, microarray studies have demonstrated that both processes can cause significant and stable up-regulation of many nuclear transcripts involved in OXHOS, even after repopulation of ρ 0 cells with wild-type mitochondria [157,158].”
From Mitochondrial DNA mutations and human disease (2010) · cites this paper as [158]
Genes involved in cellular metabolic pathways (TCA cycle, energy production, amino acid metabolism) are up-regulated in various models with mtDNA mutations (4977 bp macrodeletion, LHON m.3460G N A and m.11778G N A, m.8993T N G NARP, m.3243A N G).
“For example, genes involved in cellular metabolic pathways, such as the TCA cycle, energy production, and amino acid metabolism, are reportedly up-regulated not only in patients with the 4977 bp macrodeletion [211], but also in two lymphoblast cybrid cells containing the LHON mutations m.3460G N A (in the MT-ND1 gene) and m.11778G N A (MT-ND4 gene) [158], in a 143B osteosarcoma cybrid cell line”
From Mitochondrial DNA mutations and human disease (2010) · cites this paper as [158]

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Profiling the Mitochondrial Proteome of Leber’s Hereditary Optic Neuropathy (LHON) in Thailand: Down-Regulation of Bioenergetics and Mitochondrial Protein Quality Control Pathways in Fibroblasts with the 11778G>A Mutation
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Biochemical evidence for a mitochondrial genetic modifier in the phenotypic manifestation of Leber’s hereditary optic neuropathy-associated mitochondrial DNA mutation
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Self-citation

Authors: Danielson, S. R., Carelli, V., Tan, G., Martinuzzi, A., Schapira, A. H. V., Savontaus, M.-L., & Cortopassi, G. A.
Affiliations: University of California, Davis (US)
IRCCS Eugenio Medea (IT)
The Royal Free Hospital (GB)
University of Turku (FI)
Corresponding author: Danielson, Steven R.
ORCID: Martinuzzi, Andrea
Schapira, Anthony H. V.
Venue: Brain
Publisher: Oxford University Press (OUP)
Published: 2005-02-23
Volume: 128
Issue: 5
Pages: 1026-1037
ISSN: 0006-8950 (ISSN-L)
1460-2156
DOI: 10.1093/brain/awh447
OpenAlex: W2134563056
Cited by: 48
References: 56
Citations by year: 2026: 1 · 2023: 1 · 2021: 3 · 2020: 1 · 2018: 1 · 2017: 2 · 2016: 2 · 2014: 3 · 2013: 3 · 2012: 2
FWCI: 2.01
Type: journal article
Language: en
Open access: closed
Locations: Brain (publishedVersion)
PubMed (publishedVersion)
Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
UCL Discovery (University College London) (submittedVersion)
Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
Funders: National Institute on Aging (AG-11967, AG16719, AG23311, R01AG016719, R03AG023311, R01AG011967)
National Eye Institute (R01EY012245, EY 12245)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Aldose Reductase and Taurine
Health Sciences › Medicine › Ophthalmology › Glaucoma and retinal disorders
Keywords: Leber's hereditary optic neuropathy, mitochondrial DNA mutations, transcriptome, aldose reductase, sorbitol, oxidative phosphorylation, mitochondrial dysfunction, lymphoblasts, aldose reductase inhibitors, diabetic retinopathy
MeSH terms: Aldehyde Reductase, Cell Line, DNA, Mitochondrial, Humans, Hybrid Cells, Sorbitol, Tumor Cells, Cultured, Signal Transduction, Up-Regulation, Point Mutation, Reverse Transcriptase Polymerase Chain Reaction, Oligonucleotide Array Sequence Analysis, Optic Atrophy, Hereditary, Leber

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Isolation of transcriptomal changes attributable to LHON mutations and the cybridization process

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