Mitochondrial Base Editing: Recent Advances towards Therapeutic Opportunities

Kar, Bibekananda; Restrepo-Castillo, Santiago; Sabharwal, Ankit; Clark, Karl J.; Ekker, Stephen C.

doi:10.3390/ijms24065798

Cited by 15 publications

(5 citation statements)

References 100 publications

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“…Nevertheless, the result here suggests the mitochondrial version of humanin must be important because its peptide sequence has been conserved throughout vertebrate evolution. The nuclear versions might also be important, and they warrant further study, such as using CRISPR techniques to alter or knock out the numts, and methods of introducing base changes into mitochondrial genes are on the horizon 21 .…”

Section: Discussionmentioning

confidence: 99%

Evidence of natural selection in the mitochondrial-derived peptides humanin and SHLP6

Gruschus,

Morris,

Tjandra

2023

Sci Rep

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Mitochondrial-derived peptides are encoded by mitochondrial DNA but have biological activity outside mitochondria. Eight of these are encoded by sequences within the mitochondrial 12S and 16S ribosomal genes: humanin, MOTS-c, and the six SHLP peptides, SHLP1-SHLP6. These peptides have various effects in cell culture and animal models, affecting neuroprotection, insulin sensitivity, and apoptosis, and some are secreted, potentially having extracellular signaling roles. However, except for humanin, their importance in normal cell function is unknown. To gauge their importance, their coding sequences in vertebrates have been analyzed for synonymous codon bias. Because they lie in RNA genes, such bias should only occur if their amino acids have been conserved to maintain biological function. Humanin and SHLP6 show strong synonymous codon bias and sequence conservation. In contrast, SHLP1, SHLP2, SHLP3, and SHLP5 show no significant bias and are poorly conserved. MOTS-c and SHLP4 also lack significant bias, but contain highly conserved N-terminal regions, and their biological importance cannot be ruled out. An additional potential mitochondrial-derived peptide sequence was discovered preceding SHLP2, named SHLP2b, which also contains a highly conserved N-terminal region with synonymous codon bias.

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Section: Discussionmentioning

confidence: 99%

Evidence of natural selection in the mitochondrial-derived peptides humanin and SHLP6

Gruschus,

Morris,

Tjandra

2023

Sci Rep

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“…The second approach does not try to decrease the heteroplasmy level but simply to correct the mutated base [66]. This concept has been recently described by Kar et al [67].…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial DNA Haplogroups and Variants Predispose to Chagas Disease Cardiomyopathy

Gallardo,

Brochet,

Goudenège

et al. 2023

Hearts

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Cardiomyopathies are major causes of heart failure. Chagas disease (CD) is caused by the parasite Trypanosoma cruzi, and it is endemic in Central and South America. Thirty percent of cases evolve into chronic chagas cardiomyopathy (CCC), which has worse prognosis as compared with other cardiomyopathies. In vivo bioenergetic analysis and ex vivo proteomic analysis of myocardial tissues highlighted worse mitochondrial dysfunction in CCC, and previous studies identified nuclear-encoded mitochondrial gene variants segregating with CCC. Here, we assessed the role of the mitochondrial genome through mtDNA copy number variations and mtDNA haplotyping and sequencing from heart or blood tissues of severe, moderate CCC and asymptomatic/indeterminate Chagas disease as well as healthy controls as an attempt to help decipher mitochondrial-intrinsic genetic involvement in Chagas disease development. We have found that the mtDNA copy number was significantly lower in CCC than in heart tissue from healthy individuals, while blood mtDNA content was similar among asymptomatic Chagas disease, moderate, and severe CCC patients. An MtDNA haplogrouping study has indicated that African haplogroups were over represented in the Chagas subject groups in comparison with healthy Brazilian individuals. The European lineage is associated with protection against cardiomyopathy and the macro haplogroup H is associated with increased risk towards CCC. Using mitochondria DNA sequencing, 84 mtDNA-encoded protein sequence pathogenic variants were associated with CCC. Among them, two variants were associated to left ventricular non-compaction and two to hypertrophic cardiomyopathy. The finding that mitochondrial protein-coding SNPs and mitochondrial haplogroups associate with risk of evolving to CCC is consistent with a key role of mitochondrial DNA in the development of chronic chagas disease cardiomyopathy.

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“…The current mtDNA editing tools, such as restriction endonucleases, zinc finger nucleases (mitoZFNs), transcription activator-like effector nucleases (mitoTALENs) and mito-Tev-TALE, have many drawbacks to efficiently eliminate mutant mtDNA, thereby preventing their use in clinical setting [ 91 ]. Novel promising molecular tools, such as the protein-based editor Double-stranded DNA deaminase (DddA) [ 92 ] and mitochondrial-targeted meganucleases (mitoARCUS) [ 93 ] are being developed [ 94 ]. Thus, the technology of editing mtDNA is still years behind with lots of different types of hurdles to overcome before transitioning to clinical therapy.…”

Section: Challenges In Clinical Testing For Primary Mitochondrial Dis...mentioning

confidence: 99%

Challenges and opportunities to bridge translational to clinical research for personalized mitochondrial medicine

Gropman,

Uittenbogaard,

Chiaramello

2024

Neurotherapeutics

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Mitochondrial Base Editing: Recent Advances towards Therapeutic Opportunities

Cited by 15 publications

References 100 publications

Evidence of natural selection in the mitochondrial-derived peptides humanin and SHLP6

Evidence of natural selection in the mitochondrial-derived peptides humanin and SHLP6

Mitochondrial DNA Haplogroups and Variants Predispose to Chagas Disease Cardiomyopathy

Challenges and opportunities to bridge translational to clinical research for personalized mitochondrial medicine

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