Damage in Mitochondrial DNA Associated with Parkinson's Disease

Martín-Jiménez, Rebeca; Lurette, Olivier; Hébert-Chatelain, Étienne

doi:10.1089/dna.2020.5398

Cited by 37 publications

(25 citation statements)

References 116 publications

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“…These genes are mtDNA polymerase gamma 1 (POLG1), TFAM (discussed above), and the DNA helicase TWINKLE (TWNK). Mutations in these genes increase the risk of PD [224]. POLG1, like other polymerases, controls mtDNA synthesis, repair and replication [225]; the length of a CAG repeat in exon 2 directly correlates with function of the protein, and increased number of repeats has been associated with PD [226,227].…”

Section: Parkinson's Diseasementioning

confidence: 99%

Dysregulation of PGC-1α-Dependent Transcriptional Programs in Neurological and Developmental Disorders: Therapeutic Challenges and Opportunities

McMeekin

Fox

Boas

et al. 2021

Cells

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Substantial evidence indicates that mitochondrial impairment contributes to neuronal dysfunction and vulnerability in disease states, leading investigators to propose that the enhancement of mitochondrial function should be considered a strategy for neuroprotection. However, multiple attempts to improve mitochondrial function have failed to impact disease progression, suggesting that the biology underlying the normal regulation of mitochondrial pathways in neurons, and its dysfunction in disease, is more complex than initially thought. Here, we present the proteins and associated pathways involved in the transcriptional regulation of nuclear-encoded genes for mitochondrial function, with a focus on the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1α). We highlight PGC-1α’s roles in neuronal and non-neuronal cell types and discuss evidence for the dysregulation of PGC-1α-dependent pathways in Huntington’s Disease, Parkinson’s Disease, and developmental disorders, emphasizing the relationship between disease-specific cellular vulnerability and cell-type-specific patterns of PGC-1α expression. Finally, we discuss the challenges inherent to therapeutic targeting of PGC-1α-related transcriptional programs, considering the roles for neuron-enriched transcriptional coactivators in co-regulating mitochondrial and synaptic genes. This information will provide novel insights into the unique aspects of transcriptional regulation of mitochondrial function in neurons and the opportunities for therapeutic targeting of transcriptional pathways for neuroprotection.

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Section: Parkinson's Diseasementioning

confidence: 99%

Dysregulation of PGC-1α-Dependent Transcriptional Programs in Neurological and Developmental Disorders: Therapeutic Challenges and Opportunities

McMeekin

Fox

Boas

et al. 2021

Cells

View full text Add to dashboard Cite

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“…The mitochondrial genome, mtDNA, is a doublestranded molecule, 16 kbp in size, containing 37 genes that encode 13 polypeptides that take part in the oxidative phosphorylation chain, 2 rRNAs and 22 tRNAs, all exclusive to the mitochondria [8]. Mutations in mtDNA have been associated with multiple metabolic and neuromuscular degenerative syndromes, and connected with Parkinson's and Alzheimer's diseases, diabetes and several types of cancer [9][10][11][12][13][14][15][16][17]. The therapeutic approaches to treat mtDNA diseases have been largely ineffective, as they focus on alleviation of the symptoms.…”

Section: Introductionmentioning

confidence: 99%

Development of Peptide-Based Nanoparticles for Mitochondrial Plasmid DNA Delivery

et al. 2021

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A mitochondrion is a cellular organelle able to produce cellular energy in the form of adenosine triphosphate (ATP). As in the nucleus, mitochondria contain their own genome: the mitochondrial DNA (mtDNA). This genome is particularly susceptible to mutations that are at the basis of a multitude of disorders, especially those affecting the heart, the central nervous system and muscles. Conventional clinical practice applied to mitochondrial diseases is very limited and ineffective; a clear need for innovative therapies is demonstrated. Gene therapy seems to be a promising approach. The use of mitochondrial DNA as a therapeutic, optimized by peptide-based complexes with mitochondrial targeting, can be seen as a powerful tool in the reestablishment of normal mitochondrial function. In line with this requirement, in this work and for the first time, a mitochondrial-targeting sequence (MTS) has been incorporated into previously researched peptides, to confer on them a targeting ability. These peptides were then considered to complex a plasmid DNA (pDNA) which contains the mitochondrial gene ND1 (mitochondrially encoded NADH dehydrogenase 1 protein), aiming at the formation of peptide-based nanoparticles. Currently, the ND1 plasmid is one of the most advanced bioengineered vectors for conducting research on mitochondrial gene expression. The formed complexes were characterized in terms of pDNA complexation capacity, morphology, size, surface charge and cytotoxic profile. These data revealed that the developed carriers possess suitable properties for pDNA delivery. Furthermore, in vitro studies illustrated the mitochondrial targeting ability of the novel peptide/pDNA complexes. A comparison between the different complexes revealed the most promising ones that complex pDNA and target mitochondria. This may contribute to the optimization of peptide-based non-viral systems to target mitochondria, instigating progress in mitochondrial gene therapy.

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“…Parkinson’s disease is a progressive neurodegenerative disorder with movement problems due to the loss of dopamine-producing neurons ( Kalia and Lang, 2015 ). Interestingly, most of PD-related proteins have been shown to lead to dysfunctional mitochondria and/or accumulated damaged mitochondria ( Martin-Jimenez et al, 2020 ). Some of them, including PINK1 and Parkin and LRRK2, play important roles in the execution of mitophagy ( Vives-Bauza et al, 2010 ; Wallings et al, 2015 ).…”

Section: Mitophagy In Immunity and Human Diseasesmentioning

confidence: 99%

The Mitochondrial Response to DNA Damage

Rong

et al. 2021

Front. Cell Dev. Biol.

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Mitochondria are double membrane organelles in eukaryotic cells that provide energy by generating adenosine triphosphate (ATP) through oxidative phosphorylation. They are crucial to many aspects of cellular metabolism. Mitochondria contain their own DNA that encodes for essential proteins involved in the execution of normal mitochondrial functions. Compared with nuclear DNA, the mitochondrial DNA (mtDNA) is more prone to be affected by DNA damaging agents, and accumulated DNA damages may cause mitochondrial dysfunction and drive the pathogenesis of a variety of human diseases, including neurodegenerative disorders and cancer. Therefore, understanding better how mtDNA damages are repaired will facilitate developing therapeutic strategies. In this review, we focus on our current understanding of the mtDNA repair system. We also discuss other mitochondrial events promoted by excessive DNA damages and inefficient DNA repair, such as mitochondrial fusion, fission, and mitophagy, which serve as quality control events for clearing damaged mtDNA.

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Damage in Mitochondrial DNA Associated with Parkinson's Disease

Cited by 37 publications

References 116 publications

Dysregulation of PGC-1α-Dependent Transcriptional Programs in Neurological and Developmental Disorders: Therapeutic Challenges and Opportunities

Dysregulation of PGC-1α-Dependent Transcriptional Programs in Neurological and Developmental Disorders: Therapeutic Challenges and Opportunities

Development of Peptide-Based Nanoparticles for Mitochondrial Plasmid DNA Delivery

The Mitochondrial Response to DNA Damage

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