bims-mitran 2025-03-16 papers

Issue of 2025–03–16
two papers selected by
Andreas Kohler, Umeå University

Cell. 2025 Mar 05. pii: S0092-8674(25)00194-1. [Epub ahead of print]

Engineering mtDNA deletions by reconstituting end joining in human mitochondria.

Recent breakthroughs in the genetic manipulation of mitochondrial DNA (mtDNA) have enabled precise base substitutions and the efficient elimination of genomes carrying pathogenic mutations. However, reconstituting mtDNA deletions linked to mitochondrial myopathies remains challenging. Here, we engineered mtDNA deletions in human cells by co-expressing end-joining (EJ) machinery and targeted endonucleases. Using mitochondrial EJ (mito-EJ) and mito-ScaI, we generated a panel of clonal cell lines harboring a ∼3.5 kb mtDNA deletion across the full spectrum of heteroplasmy. Investigating these cells revealed a critical threshold of ∼75% deleted genomes, beyond which oxidative phosphorylation (OXPHOS) protein depletion, metabolic disruption, and impaired growth in galactose-containing media were observed. Single-cell multiomic profiling identified two distinct nuclear gene deregulation responses: one triggered at the deletion threshold and another progressively responding to heteroplasmy. Ultimately, we show that our method enables the modeling of disease-associated mtDNA deletions across cell types and could inform the development of targeted therapies.

Keywords: DOGMA-seq; end joining; mitochondrial pathologies; mtDNA; mtDNA deletion

DOI: https://doi.org/10.1016/j.cell.2025.02.009

Trends Cell Biol. 2025 Mar 07. pii: S0962-8924(25)00039-X. [Epub ahead of print]

Quality control of mitochondrial nucleoids.

Hao Liu, Haixia Zhuang, Du Feng.

Mitochondrial nucleoids, organized complexes that house and protect mitochondrial DNA (mtDNA), are normally confined within the mitochondrial double-membrane system. Under cellular stress conditions, particularly oxidative and inflammatory stress, these nucleoids can undergo structural alterations that lead to their aberrant release into the cytoplasm. This mislocalization of nucleoid components, especially mtDNA, can trigger inflammatory responses and cell death pathways, highlighting the critical importance of nucleoid quality control mechanisms. The release of mitochondrial nucleoids occurs through specific membrane channels and transport pathways, fundamentally disrupting cellular homeostasis. Cells have evolved multiple clearance mechanisms to manage cytoplasmic nucleoids, including nuclease-mediated degradation, lysosomal elimination, and cellular excretion. This review examines the molecular mechanisms governing nucleoid quality control and explores the delicate balance between mitochondrial biology and cellular immunity. Our analysis provides insights that could inform therapeutic strategies for mtDNA-associated diseases and inflammatory disorders.

Keywords: mitochondria; mitophagy; mtDNA; nucleoid-phagy; nucleoids

DOI: https://doi.org/10.1016/j.tcb.2025.02.005