ArticleHuman molecular genetics2015
Mitochondrial complex I deficiency leads to inflammation and retinal ganglion cell death in the Ndufs4 mouse.
Article in Human molecular genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed.
- Cell-intrinsic vulnerability and immune activation cooperate to drive degeneration in a mitochondrial complex I deficiency model of optic neuropathy.Journal of neuroinflammation · 2026Article
- Leigh Syndrome Pathomechanism Involves Region-Specific Innate Immune Activation in Ndufs4 Knockout Mice.Cellular and molecular neurobiology · 2026Article
- Pharmacological Depletion of Retinal Mononuclear Phagocytes Is Neuroprotective in a Mouse Model of Mitochondrial Optic Neuropathy.Investigative ophthalmology & visual science · 2026Article
- Sterile inflammation in LHON: mitochondrial stress, innate immune signaling, and implications for AAV gene therapy.Frontiers in immunology · 2026Review
- Oxidative Stress and Inflammatory Biomarkers in Aqueous Humor and Blood of Patients with Leber's Hereditary Optic Neuropathy.Antioxidants (Basel, Switzerland) · 2025Article
- Tipping the balance: innate and adaptive immunity in mitochondrial disease.Current opinion in immunology · 2025Review
- Caspase-11 drives macrophage hyperinflammation in models of Polg-related mitochondrial disease.Nature communications · 2025Article
- Vitamin A treatment restores vision failures arising from Leber's hereditary optic neuropathy-linked mtDNA mutation.JCI insight · 2025Article
- Mutation of CRYAB encoding a conserved mitochondrial chaperone and antiapoptotic protein causes hereditary optic atrophy.JCI insight · 2024Article
- Mitochondria transfer-based therapies reduce the morbidity and mortality of Leigh syndrome.Nature metabolism · 2024Article
- Mitochondrial translocation of TFEB regulates complex I and inflammation.EMBO reports · 2024Article
- Inflammatory and interferon gene expression signatures in patients with mitochondrial disease.Journal of translational medicine · 2023Article
- Inflammatory and interferon gene expression signatures in patients with mitochondrial disease.Research square · 2023Article
- Continuous Hypoxia Reduces Retinal Ganglion Cell Degeneration in a Mouse Model of Mitochondrial Optic Neuropathy.Investigative ophthalmology & visual science · 2022Article
- The immune system as a driver of mitochondrial disease pathogenesis: a review of evidence.Orphanet journal of rare diseases · 2022Review
- Leber Hereditary Optic Neuropathy: Molecular Pathophysiology and Updates on Gene Therapy.Biomedicines · 2022Review
- Noninvasive Ophthalmic Imaging Measures Retinal Degeneration and Vision Deficits in Ndufs4-/- Mouse Model of Mitochondrial Complex I Deficiency.Translational vision science & technology · 2022Article
- Leukocyte cytokine responses in adult patients with mitochondrial DNA defects.Journal of molecular medicine (Berlin, Germany) · 2022Article
- Ndufs4 knockout mouse models of Leigh syndrome: pathophysiology and intervention.Brain : a journal of neurology · 2022Review
- Uncoupling proteins in the mitochondrial defense against oxidative stress.Progress in retinal and eye research · 2021Review
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Authors and funding
8 authors.
Funding
Abstract
Mitochondrial complex I (NADH dehydrogenase) is a major contributor to neuronal energetics, and mutations in complex I lead to vision loss. Functional, neuroanatomical and transcriptional consequences of complex I deficiency were investigated in retinas of the Ndufs4 knockout mouse. Whole-eye ERGs and multielectrode arrays confirmed a major retinal ganglion cell functional loss at P32, and retinal ganglion cell loss at P42. RNAseq demonstrated a mild and then sharp increase in innate immune and inflammatory retinal transcripts at P22 and P33, respectively, which were confirmed with QRT-PCR. Intraperitoneal injection of the inflammogen lipopolysaccharide further reduced retinal ganglion cell function in Ndufs4 KO, supporting the connection between inflammatory activation and functional loss. Complex I deficiency in the retina clearly caused innate immune and inflammatory markers to increase coincident with loss of vision, and RGC functional loss. How complex I incites inflammation and functional loss is not clear, but could be the result of misfolded complex I generating a 'non-self' response, and induction of innate immune response transcripts was observed before functional loss at P22, including β-2 microglobulin and Cx3cr1, and during vision loss at P31 (B2m, Tlr 2, 3, 4, C1qa, Cx3cr1 and Fas). These data support the hypothesis that mitochondrial complex I dysfunction in the retina triggers an innate immune and inflammatory response that results in loss of retinal ganglion cell function and death, as in Leber's hereditary Optic Neuropathy and suggests novel therapeutic routes to counter mitochondrial defects that contribute to vision loss.
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