bims-mitran 2026-05-17 papers

Issue of 2026–05–17
three papers selected by
Andreas Kohler, Umeå University

Biochim Biophys Acta Mol Cell Res. 2026 May 13. pii: S0167-4889(26)00056-X. [Epub ahead of print] 120158

Mammalian mtDNA gene expression: Concepts learned from in vivo models.

Diana Rubalcava-Gracia, Nils-Göran Larsson.

Mammalian mitochondrial DNA (mtDNA) expression is essential for oxidative phosphorylation (OXPHOS) and its in vivo regulation requires significant refinement. Here, we review key insights from mouse models carrying genetic modifications to the mtDNA expression machinery. While in vitro studies defined the basic machinery, mouse models reveal that mitochondrial transcription often exceeds immediate needs and may not be the primary rate-limiting step for OXPHOS biogenesis. Instead, mitochondria produce a transcript surplus regulated by nucleoid compaction and post-transcriptional stabilization. This apparent excess capacity is uncoupled from protein output under basal conditions but becomes critical during physiological stress or pathology. Using current and emerging genetic tools, researchers are now deciphering how regulatory layers coordinate to sustain systemic energy demands. These lessons highlight the importance of in vivo systems for identifying regulatory control points of mtDNA expression and developing targeted therapies for mitochondrial disorders.

DOI: https://doi.org/10.1016/j.bbamcr.2026.120158

Dev Cell. 2026 May 13. pii: S1534-5807(26)00123-1. [Epub ahead of print]61(5): 1146-1161.e8

Single-molecule mitochondrial DNA imaging reveals heteroplasmy dynamics shaped by developmental bottlenecks and selection in vivo.

Rajini Chandrasegaram, Sara Gottardo, Abhilesh Dhawanjewar, Antony M Hynes-Allen, Beitong Gao, Suvagata Roy Chowdhury, Luis-Carlos Tábara, Michele Frison, Stavroula Petridi, Patrick F Chinnery, Julien Prudent, Hansong Ma, Jelle van den Ameele.

Mitochondrial DNA (mtDNA) exists in many copies per cell, with cell-to-cell variability in mutation load, which is known as heteroplasmy. Developmental and age-related expansion of heteroplasmic mtDNA mutations contributes to the pathogenesis of mitochondrial and neurodegenerative diseases. Here, we describe an approach for in situ sequence-specific detection of single mtDNA molecules (mtDNA-single-molecule fluorescent in situ hybridization [smFISH]). We apply this method to visualize and measure mtDNA and heteroplasmy levels in situ at single-cell resolution in whole-mount Drosophila tissue and cultured human cells. In Drosophila, we identify a somatic mtDNA bottleneck during neurogenesis. This amplifies heteroplasmy variability between neurons, as predicted by a mathematical bottleneck model, predisposing individual neurons to a high mutation load. However, both during neurogenesis and oogenesis, mtDNA segregation is accompanied by purifying selection, promoting wild-type (WT) over pathogenic mtDNA. mtDNA-smFISH thus elucidates how developmental cell-fate transitions, accompanied by changes in cell morphology, behavior, and metabolism, can shape the transmission and selection of deleterious mtDNA variants.

Keywords: Drosophila; bottleneck; heteroplasmy; mitochondria; mitochondrial DNA; mitochondrial disease; neurogenesis; oogenesis; purifying selection; single-molecule fluorescent in situ hybridization

DOI: https://doi.org/10.1016/j.devcel.2026.03.011

EMBO Rep. 2026 May 14.

In the absence of mitochondrial fusion unequal segregation of mitochondria drives mtDNA loss.

Lisa Dengler, Francesco Padovani, Bianca Lemke, Rebecca Brugger, Alissa Benedikt, Benedikt Westermann, Boris Maček, Kurt M Schmoller, Jennifer C Ewald.

Mitochondrial biogenesis and inheritance must be tightly coordinated with cell division to maintain mitochondrial function and cell survival. The dynamics of the mitochondrial network, including fusion and fission, are essential for mitochondrial inheritance and quality control. In budding yeast, simultaneous inhibition of both processes compromises mitochondrial DNA (mtDNA) integrity, increasing the frequency of petite cells. Loss of fusion alone completely eliminates mtDNA. Although this has been known for decades, why mtDNA is lost remained unclear. Here, we examine the effects of impaired mitochondrial fusion by depleting the mitofusin Fzo1. By analyzing over thirty thousand single cells across their cell cycles, we show that Fzo1-depletion induces rapid mitochondrial fragmentation and loss of membrane potential, followed by progressive declines in mtDNA content and growth rate. During division, Fzo1-depleted daughters inherit disproportionately large mitochondrial amounts, leaving mothers with too little. This imbalance, combined with an inability to upregulate compensatory mtDNA synthesis, drives rapid mtDNA loss. Our results reveal how fusion defects cause mtDNA loss and mitochondrial dysfunction, which might have implications for diseases linked to impaired fusion.

DOI: https://doi.org/10.1038/s44319-026-00794-5