Mitochondrial DNA damage as driver of cellular outcomes

AJP Cell Physiology, Год журнала: 2021, Номер 322(2), С. C136 - C150

Опубликована: Дек. 22, 2021

Mitochondria are primarily involved in energy production through the process of oxidative phosphorylation (OXPHOS). Increasing evidence has shown that mitochondrial function impacts a plethora different cellular activities, including metabolism, epigenetics, and innate immunity. Like nucleus, mitochondria own their genetic material, but this organellar genome is circular, present multiple copies, maternally inherited. The DNA (mtDNA) encodes 37 genes solely OXPHOS. Maintenance mtDNA, replication repair, requires import nuclear DNA-encoded proteins. Thus, completely rely on nucleus to prevent alterations. As most cells contain hundreds thousands mitochondria, it follows shear number organelles allows for buffering dysfunction—at least some extent—before tissue homeostasis becomes impaired. Only red blood lack entirely. Impaired hallmark aging disorders, neurodegenerative diseases, diabetes, cancer, autoimmunity. Although alterations processes unrelated OXPHOS, such as fusion fission, contribute disease, maintenance mtDNA integrity critical proper function. Here, we focus how damage contributes dysfunction health outcomes.

Язык: Английский

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DNA Damage, Defective DNA Repair, and Neurodegeneration in Amyotrophic Lateral Sclerosis

Frontiers in Aging Neuroscience, Год журнала: 2022, Номер 14

Опубликована: Апрель 27, 2022

DNA is under constant attack from both endogenous and exogenous sources, when damaged, specific cellular signalling pathways respond, collectively termed the "DNA damage response." Efficient repair processes are essential for viability, although they decline significantly during aging. Not surprisingly, defective now increasingly implicated in age-related neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). ALS affects upper lower motor neurons brain, brainstem spinal cord, leading to muscle wasting due denervation. pathophysiology of ALS, interestingly, number or proteins linked steadily growing. This includes TAR binding protein 43 (TDP-43), a DNA/RNA that present pathological form almost all (97%) cases ALS. Hence TDP-43 pathology central neurodegeneration this condition. Fused Sarcoma (FUS) bears structural functional similarities it also functions repair. Chromosome 9 open reading frame 72 (C9orf72) fundamental because mutations C9orf72 most frequent genetic cause related condition frontotemporal dementia, European North American populations. Genetic variants encoding other involved response (DDR) have been described FUS, SOD1, SETX, VCP, CCNF, NEK1. Here we review recent evidence highlighting as an important mechanism

Язык: Английский

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Metal Complexes in Target-Specific Anticancer Therapy: Recent Trends and Challenges

Journal of Chemistry, Год журнала: 2022, Номер 2022, С. 1 - 19

Опубликована: Май 17, 2022

Cancer is characterized by abnormal cell differentiation in or on the part of body. The most commonly used chemotherapeutic drugs are developed to target rapidly dividing cells, such as cancer but they also damage healthy epithelial cells. This has serious consequences for normal cells and become responsible development various disorders. Several strategies delivering cytotoxic cancerous sites that limit systemic toxicity other adverse effects have recently been evolved. Among them, biomolecule-conjugated metal complexes-based targeting shown tremendous advantages therapy. review focuses several chemoselective biomolecules-bound complexes prospective therapy-targeted agents. In this review, we presented details extra- intracellular mechanisms We addressed current clinical issues recent therapeutic targeted therapy may pave a way future direction

Язык: Английский

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Selective activator of human ClpP triggers cell cycle arrest to inhibit lung squamous cell carcinoma

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Ноя. 3, 2023

Chemo-activation of mitochondrial ClpP exhibits promising anticancer properties. However, we are currently unaware any studies using selective and potent activators in lung squamous cell carcinoma. In this work, report on such an activator, ZK53, which therapeutic effects carcinoma vivo. The crystal structure ZK53/ClpP complex reveals a π-π stacking effect that is essential for ligand binding selectively to the ClpP. ZK53 features simple scaffold, distinct from with rigid scaffolds, as acyldepsipeptides imipridones. treatment causes decrease electron transport chain ClpP-dependent manner, results declined oxidative phosphorylation ATP production tumor cells. Mechanistically, inhibits adenoviral early region 2 factor targets activates ataxia-telangiectasia mutated-mediated DNA damage response, eventually triggering cycle arrest. Lastly, cells xenograft autochthonous mouse models.

Язык: Английский

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The transcription factor GATA6 accelerates vascular smooth muscle cell senescence-related arterial calcification by counteracting the role of anti-aging factor SIRT6 and impeding DNA damage repair

Kidney International, Год журнала: 2023, Номер 105(1), С. 115 - 131

Опубликована: Окт. 31, 2023

Язык: Английский

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