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Pathogenic mtDNA mutations inhibit melanoma metastasis

ABSTRACT: Pathogenic mtDNA mutations inhibit melanoma metastasis

PROVIDER: PRJNA1154298 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR30478476.fastq.gz	Fastqsanger.gz
	SRR30478477.fastq.gz	Fastqsanger.gz
	SRR30478478.fastq.gz	Fastqsanger.gz
	SRR30478479.fastq.gz	Fastqsanger.gz
	SRR30478480.fastq.gz	Fastqsanger.gz

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Pathogenic mtDNA mutations inhibit melanoma metastasis

Project description:We report the transcriptome profiles of A375 melanoma tumors containing distinct mtDNA mutations. This study was performed using subcutaneous tumors implanted into NSG mice, and identifies transcriptomice changes in response to pathogenic mtDNA mutations.

2024-10-25 | GSE276027 | GEO

Pathogenic mitochondrial DNA mutations inhibit melanoma metastasis.

Project description:Mitochondrial DNA (mtDNA) mutations are frequent in cancer, yet their precise role in cancer progression remains debated. To functionally evaluate the impact of mtDNA variants on tumor growth and metastasis, we developed an enhanced cytoplasmic hybrid (cybrid) generation protocol and established isogenic human melanoma cybrid lines with wild-type mtDNA or pathogenic mtDNA mutations with partial or complete loss of mitochondrial oxidative function. Cybrids with homoplasmic levels of pathogenic mtDNA reliably established tumors despite dysfunctional oxidative phosphorylation. However, these mtDNA variants disrupted spontaneous metastasis from primary tumors and reduced the abundance of circulating tumor cells. Migration and invasion of tumor cells were reduced, indicating that entry into circulation is a bottleneck for metastasis amid mtDNA dysfunction. Pathogenic mtDNA did not inhibit organ colonization following intravenous injection. In heteroplasmic cybrid tumors, single-cell analyses revealed selection against pathogenic mtDNA during melanoma growth. Collectively, these findings experimentally demonstrate that functional mtDNA is favored during melanoma growth and supports metastatic entry into the blood.

| S-EPMC11529715 | biostudies-literature

The analysis of transcriptional profiles of cybrid cells harbouring two pathogenic mtDNA variants associated with Leigh syndrome

Project description:The analysis of transcriptional profiles of cybrid cells harbouring two pathogenic mtDNA variants associated with Leigh syndrome i.e., m.9185T>C in the mt-ATP6 gene and m.13513G>A in the mt-ND5 gene, in comparison to cybrid cells harbouring control mtDNA haplogroups or the wt m.13513G variant.

2023-04-01 | E-MTAB-11035 | biostudies-arrayexpress

Highly pathogenic influenza virus inhibit Inflammatory Responses in Monocytes via Activation of the Rar-Related Orphan Receptor Alpha (RORalpa)

Project description:Highly pathogenic influenza virus inhibit Inflammatory Responses in Monocytes via Activation of the Rar-Related Orphan Receptor Alpha (RORalpha). Low (PR8) and high pathogenic influenza viruses (FPV and H5N1) were used. Monocytes were infected with low (PR8) and high pathogenic influenza viruses (FPV and H5N1)

2013-07-01 | E-GEOD-35283 | biostudies-arrayexpress

Somatic mtDNA mutations at intermediate levels of heteroplasmy are a source of functional heterogeneity among primary leukemic cells

Project description:Purpose: Metabolic reprogramming is a key feature of cellular transformation. Although the mitochondrial genome encodes components of the electron transport chain that produce tumor-modifying metabolic signals, the contribution of somatic mtDNA mutations in cancer pathophysiology remains unclear. Here, we employed scRNA-seq to capture cell state changes associated with pathogenic, tumor-enriched mtDNA variants in primary leukemic blasts using single-cell RNA sequencing (scRNA-seq)

2025-06-02 | GSE207455 | GEO

Mesenchymal Stem Cells Transfer Mitochondria to the Cells with Virtually Absent Mitochondrial Function but Not to the Cells Harboring Pathogenic Mitochondrial DNA Mutations

Project description:It has been reported that human mesenchymal stem cells (MSCs) can transfer mitochondria to the cells with severely compromised mitochondrial function. We tested whether MSCs transfer mitochondria to the cells under several different conditions of mitochondrial dysfunction, including human pathogenic mitochondrial DNA (mtDNA) mutations. Using biochemical selection methods, we found that exponentially growing cells in restrictive media (uridine and bromodeoxyuridine [BrdU]+) after coculture of MSCs (uridine-independent and BrdU-sensitive) and 143B-derived cells with severe mitochondrial dysfunction induced by either long-term ethidium bromide treatment or short-term rhodamine 6G (R6G) treatment (uridine-dependent but BrdU-resistant). The exponentially growing cells had nuclear DNA fingerprint patterns identical to 143B, and a sequence of mtDNA identical to the MSCs. Since R6G causes rapid and irreversible damage to mitochondria without the removal of mtDNA, the mitochondrial function appears to be restored through a direct transfer of mitochondria rather than mtDNA alone. Conditioned media, which were prepared by treating mtDNA-less 143B 0 cells under uridine-free condition, induced increased chemotaxis in MSC, which was also supported by transcriptome analysis. A chemotaxis inhibitory agent blocked mitochondrial transfer phenomenon in the above condition. However, we could not find any evidence of mitochondrial transfer to the cells harboring human pathogenic mtDNA mutations (A3243G mutation or 4,977 bp deletion). Thus, the mitochondrial transfer is limited to the condition of a near total absence of mitochondrial function. Elucidation of the mechanism of mitochondrial transfer will help us create a potential “cell therapy-based mitochondrial restoration or mitochondrial gene therapy” for human diseases caused by mitochondrial dysfunction. time series

2011-11-22 | E-GEOD-33831 | biostudies-arrayexpress

Tumour mtDNA mutations drive aerobic glycolysis to enhance checkpoint blockade

Project description:Mitochondrial DNA (mtDNA) encodes essential machinery for respiration and metabolic homeostasis but is paradoxically among the most common targets of somatic mutations in the cancer genome, with truncating mutations in complex I genes being over-represented1 . While mtDNA mutations have been associated with both improved and worsened prognoses in several cancer lineages1–3, whether these mutations are drivers, or exert any functional effect on tumour biology remains controversial. Here we discover that complex I-encoding mtDNA mutations are sufficient to remodel the tumour immune landscape and therapeutic resistance to immune checkpoint blockade. Using mtDNA base editing technology we engineered recurrent truncating mutations in the mtDNA-encoded complex I gene, Mt-Nd5, into murine models of melanoma. Mechanistically, these mutations promoted utilisation of pyruvate as a terminal electron acceptor and increased glycolytic flux driven by an over-reduced NAD pool and NADH shuttling between GAPDH and MDH1, mediating a Warburg-like metabolic shift. In turn, without modifying tumour growth, this altered cancer cell-intrinsic metabolism reshaped the tumour microenvironment of mouse and human cancer in a mutation load-dependent fashion, encouraging an anti-tumour immune response. This subsequently sensitises both mouse and human cancers with high mtDNA mutant heteroplasmy to immune checkpoint blockade. Strikingly, patient lesions bearing >50% mtDNA mutation load demonstrated a >2.5-fold improved response rate to checkpoint inhibitor blockade. Taken together these data nominate mtDNA mutations as functional regulators of cancer metabolism and tumour biology, with potential for therapeutic exploitation and treatment stratification.

2023-11-08 | PXD039705 | Pride

Mammalian RNase H1 directs RNA primer formation for mtDNA replication initiation and is also necessary for precise termination of mtDNA replication

Project description:The exact in vivo role for RNase H1 in mammalian mitochondria (mtDNA) has been much debated and we show here that it is essential for processing of RNA primers to provide site-specific initiation of mtDNA replication. Without RNase H1, mtDNA replication is instead initiated at non-canonical sites and becomes impaired. Furthermore, RNase H1 is also needed for replication completion and in its absence linear deleted mtDNA molecules extending between the two origins of mtDNA replication are formed. Finally, we report the first patient with a homozygous pathogenic mutation in the hybrid-binding domain (HBD) of RNase H1 causing impaired mtDNA replication. In contrast to catalytically dead pathological variants of RNase H1, this mutant version has enhanced enzyme activity. This finding shows that the RNase H1 activity must be strictly controlled to allow proper regulation of mtDNA replication.

2022-07-13 | GSE199198 | GEO

Highly pathogenic influenza virus inhibit Inflammatory Responses in Monocytes via Activation of the Rar-Related Orphan Receptor Alpha (RORalpa)

2013-07-01 | GSE35283 | GEO

Persistent injury-induced mtDNA mutations compromise organ fitness by suppressing nucleotide biosynthesis

Project description:The mitochondrial genome is present at thousands of copies/cell in metabolically active tissues. In organs such as the kidney that are exposed to frequent sublethal insults, the impact on mitochondrial DNA (mtDNA) quality is unknown. Here we show that acute kidney injury induces a burst of persistent random mtDNA mutations (mtDNA) that impair mitochondrial function, induce fibrosis, and increase subsequent injury risk in cells, mice, and humans, implicating a feed-forward loop of accumulating mtDNA mutations driving chronic disease. Multi-omic interrogation of mtDNA settings implicates marked reduction of energy-intensive nucleotide biosynthesis. Strikingly, repletion of adenosine, but not other nucleosides, restores ATP and ameliorates injury risk via the purine biosynthetic enzyme adenylate kinase 4. mtDNA may therefore be a durable remnant of acute injuries that compromise future health and both a genetic and tissue-based indicator of organ fitness. Augmented purine biosynthesis may protect vulnerable organs from acute insults.

2025-09-20 | GSE239772 | GEO

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