bims-mitran 2026-08-16 papers

Issue of 2026–08–16
four papers selected by
Andreas Kohler, Umeå University

Protein Sci. 2026 Sep;35(9): e70763

Adaptation of OXPHOS biogenesis to cellular requirements.

Metabolic cues regulate the formation of the mitochondrial OXPHOS machinery. These regulatory processes are tightly linked to mitochondrial translation, proteolytic degradation of unassembled subunits, and the formation of supercomplexes, creating checkpoints at which nutrient availability, oxygen tension, and signaling pathways remodel OXPHOS content and activity. In particular, the cytochrome c oxidase (COX) assembly pathway is regulated at multiple steps of its biogenesis in response to cellular demands. COX consists of mitochondrially encoded catalytic core subunits and nuclear-encoded accessory subunits whose coordinated expression, cofactor insertion, and incorporation into the COX enzyme result in optimized electron transport capacity. Consequently, COX assembly depends on numerous dedicated factors and protein isoforms, many of which are expressed in a tissue-specific manner. Through these metabolically regulated processes, cells tune oxidative phosphorylation efficiency, limit reactive oxygen species production, and support context-specific metabolic programs in development, adaptation, and disease.

Keywords: Cytochrome c Oxidase; OXPHOS; mitochondria

DOI: https://doi.org/10.1002/pro.70763

Biochim Biophys Acta Mol Cell Res. 2026 Aug 12. pii: S0167-4889(26)00106-0. [Epub ahead of print] 120207

Mitochondrial RNA polyadenylation: Defining RNA fate through 3' end regulation.

Linden Muellner-Wong, William Carter, Christoph Freyer, Anna Wredenberg.

Polyadenylation is a conserved post-transcriptional RNA modification with fundamentally different consequences for RNA fate across biological systems. In bacteria, chloroplasts, and plant mitochondria, adenylation is generally associated with RNA turnover and degradation, whereas its role in metazoan mitochondria remains incompletely understood. In metazoa, polyadenylation is best known for generating complete UAA stop codons in a subset of mitochondrial mRNAs. However, this explanation does not fully account for the evolutionary conservation of the modification, its diverse RNA substrates, or the broad phenotypic consequences of disrupted polyadenylation. In this review, we re-examine RNA adenylation and propose that, in metazoan mitochondria, polyadenylation primarily establishes a permissive 3' end state that governs RNA maturation, stability, translational competence, and decay. This perspective provides a unifying explanation for the diverse functions attributed to mitochondrial polyadenylation.

Keywords: Gene expression; Mitochondria; Polyadenylation; RNA homeostasis; mtPAP

DOI: https://doi.org/10.1016/j.bbamcr.2026.120207

Biochem J. 2026 Sep 02. 483(9): 1635-1651

Structural and single-molecule insights into the core human mitochondrial DNA replisome.

Ismael Plaza-G A, Samuel Miguez-Amil, Allison M Hayes, Grzegorz L Ciesielski, Rafael Fernandez-Leiro, Borja Ibarra.

Replication of human mitochondrial DNA (mtDNA) is essential for the maintenance of oxidative phosphorylation and cellular energy homeostasis. Impairment of this process leads to mtDNA deletions, depletion, and point mutations that underlie a broad spectrum of mitochondrial diseases, as well as contributing to neurodegeneration, aging, and cancer. The core human mitochondrial replisome, composed of DNA polymerase γ (Polγ), the replicative helicase Twinkle, and the mitochondrial single-stranded DNA-binding protein (mtSSB), is the main complex responsible for replicating the mitochondrial genome through a highly coordinated yet still incompletely understood mechanism. Mutations in the nuclear genes encoding these proteins represent the most common cause of inherited disorders affecting mtDNA maintenance, underscoring the importance of understanding their coordinated molecular function. Recent advances in cryo-electron microscopy and single-molecule approaches have provided unprecedented insight into the structural organization and dynamic operation of the core components of the mitochondrial replisome. These complementary methods are establishing a quantitative mechanistic framework for understanding how the mitochondrial replisome initiates, progresses, and regulates the replication of the light and heavy strands of mtDNA. In the present review, we integrate recent structural and single-molecule findings to describe the mechanisms governing the activity of Polγ, Twinkle, and mtSSB at the mitochondrial replication fork, and discuss remaining challenges toward reconstructing a complete mechanistic model of human mtDNA replication.

Keywords: DNA replication; mitochondria; protein structure; single-molecule

DOI: https://doi.org/10.1042/BCJ20260373

Nucleic Acids Res. 2026 Aug 10. pii: gkag805. [Epub ahead of print]54(15):

The pseudouridine synthase PUSL1 modifies U39 of mitochondrial tRNAs and is linked to human neurological phenotypes.

Pedro Rebelo-Guiomar, Nadav Kra-Oz, Christopher Powell, Guillaume Jouret, Morgane Plutino, Veronique Paquis-Flucklinger, Schraga Schwartz, Aldema Sas-Chen, Michal Minczuk.

Variants in the mitochondrial and nuclear genomes are linked to a wide range of human disorders marked by impaired mitochondrial function. Among these disorders, there is a growing number of patients with variants affecting mitochondrial RNA biology. Mitochondrial transcripts are pseudouridylated, and some enzymes responsible for this modification-pseudouridine synthases (PUS)-have been identified. Although known as the 'fifth nucleotide' owing to its high abundance in transcripts, the exact cellular role of pseudouridine is still unclear. Here, we expand the group of mitochondrial PUS enzymes by demonstrating that the protein encoded by PUSL1 is an active pseudouridine synthase with mitochondrial localization. Nucleotide-resolution pseudouridine mapping (mito-Ψ-Seq) followed by primer extension analysis showed that PUSL1 selectively modifies universal position 39 of all mitochondrial transfer RNAs (tRNAs) with a uridine residue in this position. Two newly described clinical PUSL1 variants, c.704G > A (p.Arg235Gln) and c.634del, p.Glu212Argfs*26, were functionally studied, presenting defects in pseudouridylation of mt-tRNA position 39 in patient-derived material, corroborating the association of this enzyme with human pathology. Our data show that PUSL1 regulates mitochondrial RNA post-transcriptional processing and its dysfunction and could be associated with neurological phenotypes.

DOI: https://doi.org/10.1093/nar/gkag805