Biallelic Variants in ENDOG Associated with Mitochondrial Myopathy and Multiple mtDNA Deletions

Nasca, Alessia; Legati, Andrea; Meneri, Megi; Ermert, Melisa Emel; Frascarelli, Chiara; Zanetti, Nadia; Garbellini, Manuela; Comi, Giacomo Pietro; Catania, Alessia; Lamperti, Costanza; Ronchi, Dario; Ghezzi, Daniele

doi:10.3390/cells11060974

Cited by 5 publications

(2 citation statements)

References 29 publications

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“…4 ). Additionally, a case report of a patient with biallelic ENDOG mutations described a patient who had a myopathy with multiple mtDNA deletions in muscle, similar to our proband [ 36 , 48 ]. On the other hand, Endog’s IMS localisation and the absence of a mtDNA deletion phenotype in livers of Endog KO mice are plausible arguments against its involvement in the mechanism of mtDNA deletion formation in Chchd10 mutant mice (although that study analysed deletions with a southern blot, which is less sensitive than long-range PCR) [ 49 ].…”

Section: Discussionmentioning

confidence: 54%

CHCHD10 mutations induce tissue-specific mitochondrial DNA deletions with a distinct signature

Shammas,

Nie,

Gilsrud

et al. 2023

Human Molecular Genetics

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Mutations affecting the mitochondrial intermembrane space protein CHCHD10 cause human disease, but it is not known why different amino acid substitutions cause markedly different clinical phenotypes, including amyotrophic lateral sclerosis-frontotemporal dementia, spinal muscular atrophy Jokela-type, isolated autosomal dominant mitochondrial myopathy and cardiomyopathy. CHCHD10 mutations have been associated with deletions of mitochondrial DNA (mtDNA deletions), raising the possibility that these explain the clinical variability. Here, we sequenced mtDNA obtained from hearts, skeletal muscle, livers and spinal cords of WT and Chchd10 G58R or S59L knockin mice to characterise the mtDNA deletion signatures of the two mutant lines. We found that the deletion levels were higher in G58R and S59L mice than in WT mice in some tissues depending on the Chchd10 genotype, and the deletion burden increased with age. Furthermore, we observed that the spinal cord was less prone to the development of mtDNA deletions than the other tissues examined. Finally, in addition to accelerating the rate of naturally occurring deletions, Chchd10 mutations also led to the accumulation of a novel set of deletions characterised by shorter direct repeats flanking the deletion breakpoints. Our results indicate that Chchd10 mutations in mice induce tissue-specific deletions which may also contribute to the clinical phenotype associated with these mutations in humans.

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Section: Discussionmentioning

confidence: 54%

CHCHD10 mutations induce tissue-specific mitochondrial DNA deletions with a distinct signature

Shammas,

Nie,

Gilsrud

et al. 2023

Human Molecular Genetics

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“…Further, the role of critical role of ENDOG in physiological mitochondrial bioenergetics in vivo has been demonstrated, as deletion of Endog in mice resulted in hearts with depleted and dysfunctional mitochondria, resulting in impaired mitochondrial respiration [ 72 ]. In this regard it has long been suggested that ENDOG may play a critical role in mitochondrial DNA replication and repair (which would clearly impact upon OxPhos), and the recent observation of mutations in EndoG that associate with mitochondrial myopathy and multiple mtDNA deletions would strongly support this [ 73 ].…”

Section: Discussionmentioning

confidence: 99%

TET3 is a positive regulator of mitochondrial respiration in Neuro2A cells

Leon Kropf,

Albany,

Zoccarato

et al. 2024

PLoS ONE

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Ten-Eleven-Translocase (TET) enzymes contribute to the regulation of the methylome via successive oxidation of 5-methyl cytosine (5mC) to derivatives which can be actively removed by base-excision-repair (BER) mechanisms in the absence of cell division. This is particularly important in post-mitotic neurons where changes in DNA methylation are known to associate with changes in neural function. TET3, specifically, is a critical regulator of both neuronal differentiation in development and mediates dynamic changes in the methylome of adult neurons associated with cognitive function. While DNA methylation is understood to regulate transcription, little is known of the specific targets of TET3-dependent catalytic activity in neurons. We report the results of an unbiased transcriptome analysis of the neuroblastoma-derived cell line; Neuro2A, in which Tet3 was silenced. Oxidative phosphorylation (OxPhos) was identified as the most significantly down-regulated functional canonical pathway, and these findings were confirmed by measurements of oxygen consumption rate in the Seahorse bioenergetics analyser. The mRNA levels of both nuclear- and mitochondrial-encoded OxPhos genes were reduced by Tet3-silencing, but we found no evidence for differential (hydroxy)methylation deposition at these gene loci. However, the mRNA expression of genes known to be involved in mitochondrial quality control were also shown to be significantly downregulated in the absence of TET3. One of these genes; EndoG, was identified as a direct target of TET3-catalytic activity at non-CpG methylated sites within its gene body. Accordingly, we propose that aberrant mitochondrial homeostasis may contribute to the decrease in OxPhos, observed upon Tet3-downregulation in Neuro2A cells.

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Cytoplasmic Endonuclease G promotes nonalcoholic fatty liver disease via mTORC2-AKT-ACLY and endoplasmic reticulum stress

Wang,

Tan,

Liu

et al. 2023

Nat Commun

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Endonuclease G (ENDOG), a nuclear-encoded mitochondrial intermembrane space protein, is well known to be translocated into the nucleus during apoptosis. Recent studies have shown that ENDOG might enter the mitochondrial matrix to regulate mitochondrial genome cleavage and replication. However, little is known about the role of ENDOG in the cytosol. Our previous work showed that cytoplasmic ENDOG competitively binds with 14-3-3γ, which released TSC2 to repress mTORC1 signaling and induce autophagy. Here, we demonstrate that cytoplasmic ENDOG could also release Rictor from 14-3-3γ to activate the mTORC2-AKT-ACLY axis, resulting in acetyl-CoA production. Importantly, we observe that ENDOG could translocate to the ER, bind with Bip, and release IRE1a/PERK to activate the endoplasmic reticulum stress response, promoting lipid synthesis. Taken together, we demonstrate that loss of ENDOG suppresses acetyl-CoA production and lipid synthesis, along with reducing endoplasmic reticulum stress, which eventually alleviates high-fat diet-induced nonalcoholic fatty liver disease in female mice.

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Biallelic Variants in ENDOG Associated with Mitochondrial Myopathy and Multiple mtDNA Deletions

Cited by 5 publications

References 29 publications

CHCHD10 mutations induce tissue-specific mitochondrial DNA deletions with a distinct signature

CHCHD10 mutations induce tissue-specific mitochondrial DNA deletions with a distinct signature

TET3 is a positive regulator of mitochondrial respiration in Neuro2A cells

Cytoplasmic Endonuclease G promotes nonalcoholic fatty liver disease via mTORC2-AKT-ACLY and endoplasmic reticulum stress

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