bims-mitran 2026-04-05 papers

Issue of 2026–04–05
five papers selected by
Andreas Kohler, Umeå University

Mol Cell. 2026 Apr 02. pii: S1097-2765(26)00167-X. [Epub ahead of print]86(7): 1195-1196

A splicing factor's unexpected detour to the mitochondrial surface.

In this issue of Molecular Cell, Garcia et al.1 reveal an unexpected role for the splicing factor U2AF in repressing translation and influencing the localization of nuclear-encoded mitochondrial mRNAs to the outer mitochondrial membrane.

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

Autophagy. 2026 Mar 31. 1-3

Purifying selection during maternal inheritance of mammalian mtDNA depends on autophagy and bottleneck size.

Polyxeni Papadea, Nils-Göran Larsson.

Mammalian mitochondrial DNA (mtDNA) is transmitted asexually without recombination and accumulates mutations at a high rate, which eventually should cause a mutational meltdown. Two processes operating in the maternal germline, the genetic bottleneck and purifying selection, are counteracting this decline but the exact molecular mechanisms and their possible link remain incompletely understood. To address this, we investigated the role of autophagy and mtDNA copy number in shaping purifying selection during maternal mtDNA transmission. Using a carefully designed breeding strategy in mice expressing a proofreading-deficient mitochondrial DNA polymerase, we generated animals carrying random mtDNA mutations and simultaneously introduced moderately decreased or increased mtDNA copy number, or impaired autophagy. Mutation patterns in control animals closely resembled those observed in humans, showing strong purifying selection against non-synonymous mutations, particularly in oxidative phosphorylation (OXPHOS) genes. Our recent work provides new insight by identifying autophagy as a key mediator of germline purifying selection of mtDNA. Moreover, we demonstrate that mtDNA copy number directly influences the efficiency of purifying selection, revealing that these two processes are functionally interconnected.

Keywords: Bottleneck; maternal transmission; mitochondria; mitophagy; mtDNA mutations

DOI: https://doi.org/10.1080/15548627.2026.2650772

Nat Struct Mol Biol. 2026 Apr 01.

MitoPerturb-Seq identifies gene-specific single-cell responses to mitochondrial DNA depletion and heteroplasmy.

Stephen P Burr, Kathryn Auckland, Angelos Glynos, Abhilesh Dhawanjewar, Cameron Ryall, Wei Wei, Antony Hynes-Allen, Malwina Prater, Matylda Sczaniecka-Clift, Julien Prudent, Patrick F Chinnery, Jelle van den Ameele.

Mitochondria contain their own genome, mitochondrial DNA (mtDNA), which is under strict control by the cell nucleus. mtDNA occurs in many copies per cell and mutations often only affect a proportion of them, giving rise to heteroplasmy. mtDNA copy number and heteroplasmy level together shape the tissue-specific impact of mtDNA mutations, eventually giving rise to both rare mitochondrial and common neurodegenerative diseases. Here, we use MitoPerturb-Seq for CRISPR-Cas9-based, high-throughput single-cell interrogation of the nuclear genes and pathways that sense and control mtDNA copy number and heteroplasmy. We screened a panel of mtDNA maintenance genes in mouse cells with a heteroplasmic mtDNA mt-Ta mutation. This revealed both common and perturbation-specific aspects of the integrated stress response to mtDNA depletion caused by Tfam, Opa1 and Polg knockout. These responses are only partially mediated by ATF4 and cause cell-cycle stage-independent slowing of cell proliferation. MitoPerturb-Seq, thus, provides experimental insight into disease-relevant mitochondrial-nuclear interactions and may inform development of therapies targeting cell-type- and tissue-specific vulnerabilities to mitochondrial dysfunction.

DOI: https://doi.org/10.1038/s41594-026-01779-7

Redox Biol. 2026 Mar 26. pii: S2213-2317(26)00141-2. [Epub ahead of print]92 104143

Mitochondrial translational control in cardiovascular diseases: from mechanisms to therapies.

Yunong Deng, Ningning Guo, Die Li, Zhihua Wang.

Mitochondria orchestrate cardiac metabolic homeostasis, and their dysfunction constitutes a fundamental mechanism driving cardiovascular diseases (CVDs). During eukaryotic evolution, most of the mitochondrial genes required for oxidative phosphorylation (OXPHOS) function have been transferred to the nuclear genome, except for 13 genes coding for core subunits of the OXPHOS machinery. The translational regulation of these 13 genes inside mitochondria is precisely and dynamically regulated according to the external environment under diverse metabolic conditions. However, our understanding of these biological processes in CVDs remains limited. This review summarizes recent advances in the regulatory processes of mitochondrial translation, highlighting mitoribosome biogenesis, dynamic tRNA epitranscriptomic modifications, and coupling between translation and inner-membrane assembly. We additionally integrate emerging upstream regulatory mechanisms, including redox and metabolite-sensitive signaling, mitoepigenetic remodeling, and mitochondria-localized microRNA (mitomiR)-mediated control of mitochondrial RNA fate, which collectively tune translational output under stress. Moreover, this review delineates how these processes are dysregulated in major cardiovascular pathologies, including ischemia-reperfusion (I/R) injury, cardiac hypertrophy, heart failure (HF), and inherited cardiomyopathies. Emerging therapeutic strategies designed to restore translational fidelity and throughput, ranging from pharmacological interventions and metabolic tuning to precise mitochondrial gene editing, are also discussed. By repositioning mitochondrial translation from a passive marker of injury to a druggable control node, this review offers a new paradigm for targeting mitochondrial translation to preserve myocardial resilience and treat CVDs.

Keywords: Cardiovascular diseases; Mitochondrial translation; Mitoribosome; OXPHOS; tRNA modification

DOI: https://doi.org/10.1016/j.redox.2026.104143

Science. 2026 Apr 02. 392(6793): 26-28

Mitochondrial genomes on a string of pearls.

Jelle van den Ameele, Julien Prudent.

Transient membrane constrictions, or "pearling," underlie the regular spacing of mitochondrial genomes.

DOI: https://doi.org/10.1126/science.aeg3426