The fact that mitochondria have their own DNA has been known for a number of decades. However, reading that DNA is harder than the nuclear DNA. That is because there are multiple copies of the DNA in individual mitochondria as well as there being more than one mitochondrion in most cells. However, science has now developed techniques for analysing the mitochondrial DNA in quite subtle detail. In 2024 a number of interesting papers were produced which I will talk about in this post
The rate and nature of mitochondrial DNA mutations in human pedigrees is paper produced by a number of researchers in Iceland. The abstract states: We examined the rate and nature of mitochondrial DNA (mtDNA) mutations in humans using sequence data from 64,806 contemporary Icelanders from 2,548 matrilines. Based on 116,663 mother-child transmissions, 8,199 mutations were detected, providing robust rate estimates by nucleotide type, functional impact, position, and different alleles at the same position. We thoroughly document the true extent of hypermutability in mtDNA, mainly affecting the control region but also some coding-region variants. The results reveal the impact of negative selection on viable deleterious mutations, including rapidly mutating disease-associated 3243A>G and 1555A>G and pre-natal selection that most likely occurs during the development of oocytes. Finally, we show that the fate of new mutations is determined by a drastic germline bottleneck, amounting to an average of 3 mtDNA units effectively transmitted from mother to child.
This is interesting as a paper as it looks at a large number of people's mitochondrial DNA. It has been known for some time that there is a germline "bottleneck" which reduces the variation of mtDNA (Mitochondrial DNA) in the egg cells produced by mothers. What is interesting in this paper is that it appears that only around 3 copies of mtDNA are transferred initially from mother to egg. These mitochondria are then replicated in the egg. If the egg is fertilised then the general assumption is that the father's mtDNA is destroyed, but even if it is not destroyed because of the multiplication of mitochondria (and mtDNA) in the egg the quantity of paternal mtDNA would be something like at 10,000th of the number of maternal mtDNA.
Another paper in a similar topic are was Mitochondrial DNA mutations in human oocytes undergo frequency-dependent selection but do not increase with age The summary of this paper states:
Mitochondria, cellular powerhouses, harbor DNA (mtDNA) inherited from the mothers. MtDNA mutations can cause diseases, yet whether they increase with age in human germline cells—oocytes—remains understudied. Here, using highly accurate duplex sequencing of full-length mtDNA, we detected de novo mutations in single oocytes, blood, and saliva in women between 20 and 42 years of age. We found that, with age, mutations increased in blood and saliva but not in oocytes. In oocytes, mutations with high allele frequencies (≥1%) were less prevalent in coding than non-coding regions, whereas mutations with low allele frequencies (<1%) were more uniformly distributed along mtDNA, suggesting frequency-dependent purifying selection. In somatic tissues, mutations caused elevated amino acid changes in protein-coding regions, suggesting positive or destructive selection. Thus, mtDNA in human oocytes is protected against accumulation of mutations having functional consequences and with aging. These findings are particularly timely as humans tend to reproduce later in life.
What this demonstrates is that the body acts to prevent mtDNA damage in egg cells. There is, however, another paper that needs to be read with this one.
Robustness and reliability of single-cell regulatory multi-omics with deep mitochondrial mutation profiling the summary states:
The detection of mitochondrial DNA (mtDNA) mutations in single cells holds considerable potential to define clonal relationships coupled with information on cell state in humans. Previous methods focused on higher heteroplasmy mutations that are limited in number and can be influenced by functional selection, introducing biases for lineage tracing. Although more challenging to detect, intermediate to low heteroplasmy mtDNA mutations are valuable due to their high diversity, abundance, and lower propensity to selection. To enhance mtDNA mutation detection and facilitate fine-scale lineage tracing, we developed the single-cell Regulatory multi-omics with Deep Mitochondrial mutation profiling (ReDeeM) approach, an integrated experimental and computational framework. Recently, some concerns have been raised about the analytical workflow in the ReDeeM framework. Specifically, it was noted that the mutations detected in a single molecule per cell are enriched on edges of mtDNA molecules, suggesting they resemble artifacts reported in other sequencing approaches. It was then proposed that all mutations found in one molecule per cell should be removed. We detail our error correction method, demonstrating that the observed edge mutations are distinct from previously reported sequencing artifacts. We further show that the proposed removal leads to massive elimination of bona fide and informative mutations. Indeed, mutations accumulating on edges impact a minority of all mutation calls (for example, in hematopoietic stem cells, the excess mutations on the edge account for only 4.3%−7.6% of the total). Recognizing the value of addressing edge mutations even after applying consensus correction, we provide an additional filtering option in the ReDeeM-R package. This approach effectively eliminates the position biases, leads to a mutational signature indistinguishable from bona fide mitochondrial mutations, and removes excess low molecule high connectedness mutations. Importantly, this option preserves the large majority of unique mutations identified by ReDeeM, maintaining the ability of ReDeeM to provide a more than 10-fold increase in variant detection compared to previous methods. Additionally, the cells remain well-connected. While there is room for further refinement in mutation calling strategies, the significant advances and biological insights provided by the ReDeeM framework are unique and remain intact. We hope that this detailed discussion and analysis enables the community to employ this approach and contribute to its further development.
This paper argues that there are actually quite a few mtDNA mutations that are single mutations that are ignored as test artefacts, but in fact are real and need to be taken into account. This leads to the conclusion that the paper looking at mtDNA damage in egg cells (oocytes) has ignored some minor mutations and perhaps the conclusion should be that egg cells are to a limited extent protected from mtDNA damage, but mtDNA damage still occurs at a much slower rate. This would be logical if mtDNA damage is seen to be a consequent of metabolism (in that every so often mitochondria produce reactive molecules which sometimes damage the mtDNA).
All of this tends to point at mtDNA damage being the underlying driver of development. As the mitochondria become less efficient then the cells produce different proteins. Although this initially causes phases of development at a much later stage it is part of causing the aging process. The existance of senescent cells is I think a second basic cause of the aging process that operates through the same pathway of acetylation of the histone. (see other posts).
The rate and nature of mitochondrial DNA mutations in human pedigrees is paper produced by a number of researchers in Iceland. The abstract states: We examined the rate and nature of mitochondrial DNA (mtDNA) mutations in humans using sequence data from 64,806 contemporary Icelanders from 2,548 matrilines. Based on 116,663 mother-child transmissions, 8,199 mutations were detected, providing robust rate estimates by nucleotide type, functional impact, position, and different alleles at the same position. We thoroughly document the true extent of hypermutability in mtDNA, mainly affecting the control region but also some coding-region variants. The results reveal the impact of negative selection on viable deleterious mutations, including rapidly mutating disease-associated 3243A>G and 1555A>G and pre-natal selection that most likely occurs during the development of oocytes. Finally, we show that the fate of new mutations is determined by a drastic germline bottleneck, amounting to an average of 3 mtDNA units effectively transmitted from mother to child.
This is interesting as a paper as it looks at a large number of people's mitochondrial DNA. It has been known for some time that there is a germline "bottleneck" which reduces the variation of mtDNA (Mitochondrial DNA) in the egg cells produced by mothers. What is interesting in this paper is that it appears that only around 3 copies of mtDNA are transferred initially from mother to egg. These mitochondria are then replicated in the egg. If the egg is fertilised then the general assumption is that the father's mtDNA is destroyed, but even if it is not destroyed because of the multiplication of mitochondria (and mtDNA) in the egg the quantity of paternal mtDNA would be something like at 10,000th of the number of maternal mtDNA.
Another paper in a similar topic are was Mitochondrial DNA mutations in human oocytes undergo frequency-dependent selection but do not increase with age The summary of this paper states:
Mitochondria, cellular powerhouses, harbor DNA (mtDNA) inherited from the mothers. MtDNA mutations can cause diseases, yet whether they increase with age in human germline cells—oocytes—remains understudied. Here, using highly accurate duplex sequencing of full-length mtDNA, we detected de novo mutations in single oocytes, blood, and saliva in women between 20 and 42 years of age. We found that, with age, mutations increased in blood and saliva but not in oocytes. In oocytes, mutations with high allele frequencies (≥1%) were less prevalent in coding than non-coding regions, whereas mutations with low allele frequencies (<1%) were more uniformly distributed along mtDNA, suggesting frequency-dependent purifying selection. In somatic tissues, mutations caused elevated amino acid changes in protein-coding regions, suggesting positive or destructive selection. Thus, mtDNA in human oocytes is protected against accumulation of mutations having functional consequences and with aging. These findings are particularly timely as humans tend to reproduce later in life.
What this demonstrates is that the body acts to prevent mtDNA damage in egg cells. There is, however, another paper that needs to be read with this one.
Robustness and reliability of single-cell regulatory multi-omics with deep mitochondrial mutation profiling the summary states:
The detection of mitochondrial DNA (mtDNA) mutations in single cells holds considerable potential to define clonal relationships coupled with information on cell state in humans. Previous methods focused on higher heteroplasmy mutations that are limited in number and can be influenced by functional selection, introducing biases for lineage tracing. Although more challenging to detect, intermediate to low heteroplasmy mtDNA mutations are valuable due to their high diversity, abundance, and lower propensity to selection. To enhance mtDNA mutation detection and facilitate fine-scale lineage tracing, we developed the single-cell Regulatory multi-omics with Deep Mitochondrial mutation profiling (ReDeeM) approach, an integrated experimental and computational framework. Recently, some concerns have been raised about the analytical workflow in the ReDeeM framework. Specifically, it was noted that the mutations detected in a single molecule per cell are enriched on edges of mtDNA molecules, suggesting they resemble artifacts reported in other sequencing approaches. It was then proposed that all mutations found in one molecule per cell should be removed. We detail our error correction method, demonstrating that the observed edge mutations are distinct from previously reported sequencing artifacts. We further show that the proposed removal leads to massive elimination of bona fide and informative mutations. Indeed, mutations accumulating on edges impact a minority of all mutation calls (for example, in hematopoietic stem cells, the excess mutations on the edge account for only 4.3%−7.6% of the total). Recognizing the value of addressing edge mutations even after applying consensus correction, we provide an additional filtering option in the ReDeeM-R package. This approach effectively eliminates the position biases, leads to a mutational signature indistinguishable from bona fide mitochondrial mutations, and removes excess low molecule high connectedness mutations. Importantly, this option preserves the large majority of unique mutations identified by ReDeeM, maintaining the ability of ReDeeM to provide a more than 10-fold increase in variant detection compared to previous methods. Additionally, the cells remain well-connected. While there is room for further refinement in mutation calling strategies, the significant advances and biological insights provided by the ReDeeM framework are unique and remain intact. We hope that this detailed discussion and analysis enables the community to employ this approach and contribute to its further development.
This paper argues that there are actually quite a few mtDNA mutations that are single mutations that are ignored as test artefacts, but in fact are real and need to be taken into account. This leads to the conclusion that the paper looking at mtDNA damage in egg cells (oocytes) has ignored some minor mutations and perhaps the conclusion should be that egg cells are to a limited extent protected from mtDNA damage, but mtDNA damage still occurs at a much slower rate. This would be logical if mtDNA damage is seen to be a consequent of metabolism (in that every so often mitochondria produce reactive molecules which sometimes damage the mtDNA).
All of this tends to point at mtDNA damage being the underlying driver of development. As the mitochondria become less efficient then the cells produce different proteins. Although this initially causes phases of development at a much later stage it is part of causing the aging process. The existance of senescent cells is I think a second basic cause of the aging process that operates through the same pathway of acetylation of the histone. (see other posts).
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