bims-mitran 2022-02-13 papers

Issue of 2022–02–13
two papers selected by
Andreas Kohler, Stockholm University

Nat Commun. 2022 Feb 08. 13(1): 750

In vivo mitochondrial base editing via adeno-associated viral delivery to mouse post-mitotic tissue.

Pedro Silva-Pinheiro, Pavel A Nash, Lindsey Van Haute, Christian D Mutti, Keira Turner, Michal Minczuk.

Mitochondria host key metabolic processes vital for cellular energy provision and are central to cell fate decisions. They are subjected to unique genetic control by both nuclear DNA and their own multi-copy genome - mitochondrial DNA (mtDNA). Mutations in mtDNA often lead to clinically heterogeneous, maternally inherited diseases that display different organ-specific presentation at any stage of life. For a long time, genetic manipulation of mammalian mtDNA has posed a major challenge, impeding our ability to understand the basic mitochondrial biology and mechanisms underpinning mitochondrial disease. However, an important new tool for mtDNA mutagenesis has emerged recently, namely double-stranded DNA deaminase (DddA)-derived cytosine base editor (DdCBE). Here, we test this emerging tool for in vivo use, by delivering DdCBEs into mouse heart using adeno-associated virus (AAV) vectors and show that it can install desired mtDNA edits in adult and neonatal mice. This work provides proof-of-concept for use of DdCBEs to mutagenize mtDNA in vivo in post-mitotic tissues and provides crucial insights into potential translation to human somatic gene correction therapies to treat primary mitochondrial disease phenotypes.

DOI: https://doi.org/10.1038/s41467-022-28358-w

Biochim Biophys Acta Mol Cell Res. 2022 Feb 04. pii: S0167-4889(22)00024-6. [Epub ahead of print] 119233

The fate of damaged mitochondrial DNA in the cell.

Siyang Liao, Li Chen, Zhiyin Song, He He.

Mitochondrion is a double membrane organelle that is responsible for cellular respiration and production of most of the ATP in eukaryotic cells. Mitochondrial DNA (mtDNA) is the genetic material carried by mitochondria, which encodes some essential subunits of respiratory complexes independent of nuclear DNA. Normally, mtDNA binds to certain proteins to form a nucleoid that is stable in mitochondria. Nevertheless, a variety of physiological or pathological stresses can cause mtDNA damage, and the accumulation of damaged mtDNA in mitochondria leads to mitochondrial dysfunction, which triggers the occurrence of mitochondrial diseases in vivo. In response to mtDNA damage, cell initiates multiple pathways including mtDNA repair, degradation, clearance and release, to recover mtDNA, and maintain mitochondrial quality and cell homeostasis. In this review, we provide our current understanding of the fate of damaged mtDNA, focus on the pathways and mechanisms of removing damaged mtDNA in the cell.

Keywords: Mitochondria DNA (mtDNA); Mitocytosis; Mitophagy; mtDNA release

DOI: https://doi.org/10.1016/j.bbamcr.2022.119233