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Mitochondrial ribosomal RNA is the target of functionally dominant hotspot mutations in cancer

ABSTRACT: The vast majority of recurrent somatic mutations arising in tumors affect protein-coding genes in the nuclear genome. Here, through population-scale analysis of 14,079 whole tumor genomes, we report the discovery of highly recurrent mutations affecting both the small (12S, MT-RNR1) and large (16S, MT-RNR2) RNA subunits of the mitochondrial ribosome. Compared to non-hotspot positions, mitochondrial rRNA hotspots preferentially affected positions participating in Watson-Crick base pairing and tended to arise at positions under strong purifying selection in the germline. Using precision mtDNA base editing, we engineered models of an exemplar MT-RNR1 hotspot mutation, m.1227G>A. Multimodal profiling revealed a heteroplasmy-dependent decrease in mitochondrial function and loss of respiratory chain subunits from a heteroplasmic dosage of ~10%, which were corroborated with single cell profiling of mtDNA heteroplasmy and gene expression. Mutation of evolutionarily conserved and germline constrained positions in ribosomal RNA that disrupt mitochondrial translation therefore represent a novel class of functionally dominant, pathogenic mtDNA mutations that are under positive selection in cancer genomes.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture, Osteocyte

DISEASE(S): Osteosarcoma

SUBMITTER: Sergio Lilla

LAB HEAD: Sara Rossana Zanivan

PROVIDER: PXD057390 | Pride | 2025-09-11

REPOSITORIES: Pride

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			Action	DRS
	20231010_SEL_HF_SA_JAT_R27_060923_TMT10_f001.raw	Raw
	20231010_SEL_HF_SA_JAT_R27_060923_TMT10_f002.raw	Raw
	20231010_SEL_HF_SA_JAT_R27_060923_TMT10_f003.raw	Raw
	20231010_SEL_HF_SA_JAT_R27_060923_TMT10_f004.raw	Raw
	20231010_SEL_HF_SA_JAT_R27_060923_TMT10_f005.raw	Raw

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Mitochondrial ribosomal RNA is the target of functionally dominant hotspot mutations in cancer

Project description:The vast majority of recurrent somatic mutations arising in tumors affect protein-coding genes in the nuclear genome. Here, through population-scale analysis of 14,079 whole tumor genomes, we report the discovery of highly recurrent mutations affecting both the small (12S, MT-RNR1) and large (16S, MT-RNR2) RNA subunits of the mitochondrial ribosome. Compared to non-hotspot positions, mitochondrial rRNA hotspots preferentially affected positions participating in Watson-Crick base pairing and tended to arise at positions under strong purifying selection in the germline. Using precision mtDNA base editing, we engineered models of an exemplar MT-RNR1 hotspot mutation, m.1227G>A. Multimodal profiling revealed a heteroplasmy-dependent decrease in mitochondrial function and loss of respiratory chain subunits from a heteroplasmic dosage of ~10%, which were corroborated with single cell profiling of mtDNA heteroplasmy and gene expression. Mutation of evolutionarily conserved and germline constrained positions in ribosomal RNA that disrupt mitochondrial translation therefore represent a novel class of functionally dominant, pathogenic mtDNA mutations that are under positive selection in cancer genomes.

2024-11-05 | MSV000096292 | MassIVE

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

Tumour mtDNA mutations drive aerobic glycolysis to enhance checkpoint blockade (part 2)

2023-11-08 | PXD044987 | Pride

Definition of the composition of the mitochondrial nucleoid in mice

Project description:Mitochondrial DNA (mtDNA) is compacted into dynamic structures called mitochondrial nucleoids (mt-nucleoids), with the mitochondrial transcription factor A (TFAM) as the core packaging protein. We generated Tfam-FLAGBAC mice to investigate the mt-nucleoid composition in vivo. Importantly, we showed that the TFAM-FLAG protein is functional and complements the absence of the wild-type TFAM. We identified proteins as core mt-nucleoid components by proteomics analysis of Tfam-FLAGBAC mice. Surprisingly, the mitoribosome subunit MRPS38 was part of the mt-nucleoid, and its downregulation led to the increase of mtDNA replication and transcription. Thus, MRPS38 might have a novel function repressing mtDNA expression. Also, we identified proteins that may stabilize TFAM-FLAG upon depletion of the mitochondrial RNA polymerase despite the absence of mtDNA and induction of the LONP1 protease. Finally, we evaluated the changes in mt-nucleoids caused by very high levels of TFAM-FLAG and discovered eight new interactors that could counteract the high TFAM levels to maintain active mtDNA transcription. Altogether, we demonstrate that the Tfam-FLAGBAC mice are a valuable tool for investigating the mt-nucleoid composition in vivo.

2025-09-23 | PXD047950 | Pride

Single-Mitochondrion Sequencing Uncovers Distinct Mutational Patterns and Heteroplasmy Landscape in Mouse Astrocytes and Neurons

Project description:BACKGROUND: Mitochondrial (mt) heteroplasmy can cause adverse biological consequences when deleterious mtDNA mutations accumulate disrupting ‘normal’ mt-driven processes and cellular functions. To investigate the heteroplasmy of such mtDNA changes we developed a moderate throughput mt isolation procedure to quantify the mt single-nucleotide variant (SNV) landscape in individual mouse neurons and astrocytes In this study we amplified mt-genomes from 1,645 single mitochondria (mts) isolated from mouse single astrocytes and neurons to 1. determine the distribution and proportion of mt-SNVs as well as mutation pattern in specific target regions across the mt-genome,2. assess differences in mtDNA SNVs between neurons and astrocytes, and 3. Study cosegregation of variants in the mouse mtDNA. RESULTS: 1. The data show that specific sites of the mt-genome are permissive to SNV presentation while others appear to be under stringent purifying selection. Nested hierarchical analysis at the levels of mitochondrion, cell, and mouse reveals distinct patterns of inter- and intra-cellular variation for mt-SNVs at different sites. 2. Further, differences in the SNV incidence were observed between mouse neurons and astrocytes for two mt-SNV 9027:G>A and 9419:C>T showing variation in the mutational propensity between these cell types. Purifying selection was observed in neurons as shown by the Ka/Ks statistic, suggesting that neurons are under stronger evolutionary constraint as compared to astrocytes. 3. Intriguingly, these data show strong linkage between the SNV sites at nucleotide positions 9027 and 9461. CONCLUSION: This study suggests that segregation as well as clonal expansion of mt-SNVs is specific to individual genomic loci, which is important foundational data in understanding of heteroplasmy and disease thresholds for mutation of pathogenic variants.

2024-06-24 | GSE218122 | GEO

Regulatory principles of human mitochondrial gene expression revealed by kinetic analysis of the RNA life cycle

Project description:Mitochondria play a critical role in cellular metabolism primarily through hosting the oxidative phosphorylation (OXPHOS) machinery that is encoded by mitochondrial DNA (mtDNA) and nuclear DNA, with each gene expression system being regulated by a distinct set of mechanisms. In this study, we performed a quantitative analysis of the mitochondrial messenger RNA (mt-mRNA) life cycle to gain insights into the principles underlying the regulation of mtDNA-encoded protein abundance. Our analysis revealed a unique balance between the rapid turnover and high accumulation of mt-mRNA, leading to a 700-fold higher transcriptional output compared to nuclear-encoded OXPHOS genes. Additionally, we observed that mt-mRNA processing and its association to the mitochondrial ribosome occur rapidly and that these processes are linked mechanistically. These data resulted in a model of mtDNA expression that is predictive across cell lines, revealing that differential turnover and translation efficiencies are the major contributors to mitochondrial-encoded protein synthesis. Applying this framework to a disease model of Leigh syndrome, French–Canadian type, we found that the responsible nuclear-encoded gene, LRPPRC, disrupts OXPHOS biogenesis predominantly through altering mt-mRNA stability. Our findings provide a comprehensive view of the intricate regulatory mechanisms governing mtDNA-encoded protein synthesis, highlighting the importance of quantitatively analyzing the mitochondrial RNA life cycle for decoding the regulatory principles of mtDNA expression.

2025-01-21 | GSE224662 | GEO

Selective elimination of mitochondria mutations in the germline by genome editing

Project description:Currently there is no treatment for mitochondrial disease, a group of devastating inherited disorders caused by mutations in mitochondrial DNA (mtDNA). Here we report a strategy to prevent the germline transmission of mitochondrial diseases. This technique is based on the specific elimination of mutated mtDNA through the use of mitochondria targeted nucleases. Our approaches represent a potential therapeutic avenue for preventing the transgenerational transmission of human mitochondrial diseases caused by mutations in mtDNA. A total of 4 samples were analyzed. Test samples were compared to sex-matched reference samples.

2015-04-23 | E-GEOD-67371 | biostudies-arrayexpress

Effect of QTRT2 KO on mitochondrial translation

Project description:Mitochondria are organelles that generate most of the energy in eukaryotic cells in the form of ATP via oxidative phosphorylation in eukaryote. Twenty-two species of mitochondrial (mt-)tRNAs encoded in mtDNA are required to translate essential subunits of the respiratory chain complexes involved in oxidative phosphorylation. mt-tRNAs contain post-transcriptional modifications introduced by nuclear-encoded tRNA-modifying enzymes. These modifications are required for deciphering genetic code accurately, as well as stabilizing tRNA. Loss of tRNA modifications frequently results in severe pathological consequences. We performed a comprehensive analysis of post-transcriptional modifications of all human mt-tRNAs, including 14 previously-uncharacterized species, and revised the modification status of some of the previously studied species. In total, we found 17 kinds of RNA modifications at 137 positions (8.7% in 1,575 nucleobases) in 22 species of human mt-tRNAs. An up-to-date list of 34 genes responsible for human mt-tRNA modifications are provided. We here demonstrated that both QTRT1 and QTRT2 are required for biogenesis of queuosine (Q) at position 34 of four mt-tRNAs. Our results provide insight into the molecular mechanisms underlying the mitochondrial decoding system, and could help to elucidate the molecular pathogenesis of human mitochondrial diseases caused by aberrant tRNA modifications.

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Project description:Mitochondrial complex I, the largest enzyme complex of the mitochondrial oxidative phosphorylation machinery, has been proposed to contribute to variety of age-related pathological alterations as well as longevity. The enzyme complex-consisting proteins are encoded by both nuclear- (nDNA) and mitochondrial DNA (mtDNA). While some association studies of mtDNA-encoded complex I genes and lifespan in humans have been reported, experimental evidence and functional consequence of such variants are limited to studies using invertebrate models. Here, we present experimental evidence that a homoplasmic mutation in mitochondrially encoded complex I gene, mt-Nd2, modulates lifespan by altering cellular tryptophan levels and consequently ageing-related pathways in mice. A conplastic mouse strain carrying a mutation at m.4738C>A in mt-Nd2 lived significantly shorter than the controls. The same mutation led to higher susceptibility to glucose intolerance induced by high fat diet feeding. These phenotypes were not observed in mice carrying a mutation in another mtDNA-encoded complex I gene, mt-Nd5, suggesting functional relevance of particular mutations in complex I to ageing and age-related diseases.

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