Expression of expanded FMR1-CGG repeats alters mitochondrial miRNAs and modulates mitochondrial functions and cell death in cellular model of FXTAS

Gohel, Dhruv; Sripada, Lakshmi; Prajapati, Paresh; Currim, Fatema; Roy, Milton; Singh, Kritarth; Shinde, Anjali; Mane, Minal; Kotadia, Darshan; Tassone, Flora; Charlet‐Berguerand, Nicolas; Singh, Rajesh

doi:10.1016/j.freeradbiomed.2021.01.038

Cited by 13 publications

(6 citation statements)

References 48 publications

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“…In our investigation, we found no genetic evidence of such disorders or other diseases related to nuclear gene mutations in this patient. In FXTAS, expanded CGG repeats (FMRpolyG) affect mitochondria by reducing ATP levels, mitochondrial transmembrane potential, mitochondrial supercomplex assemblies and activities, and the expression of mitochondrial DNA-encoded transcripts (15), as well as by altering the translocation of mitochondrial microRNAs (16). In addition, the association between the development of FXTAS among FMR1 premutation carriers (55 to 200 CGG repeats) and higher rates of mitochondrial DNA variants is evident (17).…”

Section: Discussionmentioning

confidence: 99%

Myoclonic Epilepsy with Ragged-red Fibers with Intranuclear Inclusions

et al. 2022

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We herein report a case of myoclonic epilepsy with ragged-red fibers (MERRF) harboring a novel variant in mitochondrial cysteine transfer RNA (MT-TC). A 68-year-old woman presented with progressive myoclonic epilepsy with optic atrophy and peripheral neuropathy. A skin biopsy revealed p62-positive intranuclear inclusions. No mutations were found in the causative genes for diseases known to be related to intranuclear inclusions; however, a novel variant in MT-TC was found. The association between intranuclear inclusions and this newly identified MERRF-associated variant is unclear; however, the rare complication of intranuclear inclusions in a patient with typical MERRF symptoms should be noted for future studies.

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Section: Discussionmentioning

confidence: 99%

Myoclonic Epilepsy with Ragged-red Fibers with Intranuclear Inclusions

et al. 2022

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“…In addition, it is also feasible that the supply of nuclear-encoded mitochondrial genes is compromised [151]. More recently, it has been described that expression of FMRpolyG in the HEK293 cell line can altered the content of nuclear-encoded miRNAs in whole cellular preparations but also in mitochondrial fractions [152], indicating that the altered biogenesis of miRNAs in CGG PM conditions (as we will discuss in brief) also affect mitochondrial functions. However, some miRNAs were enriched in the mitochondria but depleted in whole cell lysates, as in the case of miR-320a, which translocation into the HEK293 mitochondria was apparently increased in response to CGG PM conditions in an attempt to restore mitochondrial functions but failing to form the functional RISC complexes with Argonaute 2 (Ago2) required for regulation of mitochondrial transcripts [152].…”

Section: Mitochondrial Dysfunction and Overproduction Of Reactive Oxygen Species In Premutation Carriersmentioning

confidence: 93%

Molecular Pathogenesis and Peripheral Monitoring of Adult Fragile X-Associated Syndromes

Valor

Morales

Hervás-Corpión

et al. 2021

IJMS

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Abnormal trinucleotide expansions cause rare disorders that compromise quality of life and, in some cases, lifespan. In particular, the expansions of the CGG-repeats stretch at the 5’-UTR of the Fragile X Mental Retardation 1 (FMR1) gene have pleiotropic effects that lead to a variety of Fragile X-associated syndromes: the neurodevelopmental Fragile X syndrome (FXS) in children, the late-onset neurodegenerative disorder Fragile X-associated tremor-ataxia syndrome (FXTAS) that mainly affects adult men, the Fragile X-associated primary ovarian insufficiency (FXPOI) in adult women, and a variety of psychiatric and affective disorders that are under the term of Fragile X-associated neuropsychiatric disorders (FXAND). In this review, we will describe the pathological mechanisms of the adult “gain-of-function” syndromes that are mainly caused by the toxic actions of CGG RNA and FMRpolyG peptide. There have been intensive attempts to identify reliable peripheral biomarkers to assess disease progression and onset of specific pathological traits. Mitochondrial dysfunction, altered miRNA expression, endocrine system failure, and impairment of the GABAergic transmission are some of the affectations that are susceptible to be tracked using peripheral blood for monitoring of the motor, cognitive, psychiatric and reproductive impairment of the CGG-expansion carriers. We provided some illustrative examples from our own cohort. Understanding the association between molecular pathogenesis and biomarkers dynamics will improve effective prognosis and clinical management of CGG-expansion carriers.

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“…For instance, Zhang et al (2014) demonstrated that miR-1, which is upregulated during myogenesis, can effectively penetrate mitochondria by forming a complex with Ago2, thereby enhancing the translation of mitochondrial-encoded transcripts. Gohel et al (2021) investigated the role of mitochondrial miRNAs in the pathogenesis of Fragile X-associated tremor/ ataxia syndrome (FXTAS). In their study, miR-320a was found to associate with Ago2 in HEK293 cells exhibiting expanded CGG repeats, with a notable enrichment of this complex within the mitochondrial matrix.…”

Section: Transportation Of Mirna Into Mitochondriamentioning

confidence: 99%

Mitochondrial-related microRNAs and their roles in cellular senescence

Luo,

An,

Xiao

et al. 2024

Front. Physiol.

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Aging is a natural aspect of mammalian life. Although cellular mortality is inevitable, various diseases can hasten the aging process, resulting in abnormal or premature senescence. As cells age, they experience distinctive morphological and biochemical shifts, compromising their functions. Research has illuminated that cellular senescence coincides with significant alterations in the microRNA (miRNA) expression profile. Notably, a subset of aging-associated miRNAs, originally encoded by nuclear DNA, relocate to mitochondria, manifesting a mitochondria-specific presence. Additionally, mitochondria themselves house miRNAs encoded by mitochondrial DNA (mtDNA). These mitochondria-residing miRNAs, collectively referred to as mitochondrial miRNAs (mitomiRs), have been shown to influence mtDNA transcription and protein synthesis, thereby impacting mitochondrial functionality and cellular behavior. Recent studies suggest that mitomiRs serve as critical sensors for cellular senescence, exerting control over mitochondrial homeostasis and influencing metabolic reprogramming, redox equilibrium, apoptosis, mitophagy, and calcium homeostasis-all processes intimately connected to senescence. This review synthesizes current findings on mitomiRs, their mitochondrial targets, and functions, while also exploring their involvement in cellular aging. Our goal is to shed light on the potential molecular mechanisms by which mitomiRs contribute to the aging process.

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Expression of expanded FMR1-CGG repeats alters mitochondrial miRNAs and modulates mitochondrial functions and cell death in cellular model of FXTAS

Cited by 13 publications

References 48 publications

Myoclonic Epilepsy with Ragged-red Fibers with Intranuclear Inclusions

Myoclonic Epilepsy with Ragged-red Fibers with Intranuclear Inclusions

Molecular Pathogenesis and Peripheral Monitoring of Adult Fragile X-Associated Syndromes

Mitochondrial-related microRNAs and their roles in cellular senescence

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