bims-mitran 2026-08-02 papers

Issue of 2026–08–02
three papers selected by
Andreas Kohler, Umeå University

Proc Natl Acad Sci U S A. 2026 Aug 04. 123(31): e2608102123

Cryoelectron tomography reveals an age-related decline in mitoribosomes that contributes to T cell dysfunction in older individuals.

Jingwen Chen, Lili Su, Bangze Pan, Junhao Sang, Linlin Li, Junsong Huang, Zhao-Lan Hu, Lixin Wang, Xiaojie Zhang, Jun Jin.

Mitochondrial dysfunction drives T cell aging in mice. Yet, due to fundamental differences in T cell aging mechanisms between species, whether human T cells exhibit similar mitochondrial alterations remains unclear, with existing evidence often conflicting. Using cryoelectron tomography, we resolved the structure and spatial organization of mitochondrial ribosomes in primary human CD8+ T cells under physiological conditions. Comparative analysis with human aging models revealed an age-related reduction in mitoribosome abundance and in higher-order mitoribosome organization, which is necessary for cooperative translation. Defective mitochondrial translation suppressed cytosolic ribosomal protein expression, thereby limiting mitochondrial biogenesis. The consequent reduction in mitochondrial mass induced an aged T cell phenotype characterized by compromised memory phenotypes and proliferative capacity. Enhancing mitochondrial translation via overexpression of the mitoribosomal component Mrps5 reversed aged T cell phenotypes in a mouse model of viral infection or tumor. Together, our findings provide nanoscale-resolution views of internal mitochondrial structures in situ, revealing an age-related loss of mitoribosomes. This loss contributes to mitochondrial dysfunction and the subsequent decline in T cell function observed in older individuals. Restoring mitochondrial translation may therefore represent a strategy for mitigating T cell dysfunction in the aging population.

Keywords: T cell aging; cryo-electron tomography; mitoribosome

DOI: https://doi.org/10.1073/pnas.2608102123

bioRxiv. 2026 Jul 17. pii: 2026.07.16.738964. [Epub ahead of print]

MTERF1 loss buffers against pathogenic mtDNA deletions through transcriptional regulation.

Tamar Kavlashvili, Elim Choi, Ruobing Cui, Juan C Landoni, Simon Zhang, Stefan Isaac, Stirling Churchman, Suliana Manley, Craig Thompson, Agnel Sfeir.

Large-scale mitochondrial DNA (mtDNA) deletions cripple oxidative phosphorylation once they exceed a critical heteroplasmy threshold, causing incurable mitochondrial pathologies. Using a genome-wide CRISPR/Cas9 screen in an engineered human cell line carrying a large-scale mtDNA deletion at high heteroplasmy, we identified mitochondrial transcription termination factor 1 (MTERF1) as a suppressor of the heteroplasmy burden. Loss of MTERF1 restored mitochondrial function and increased cellular proliferation in cells with a mtDNA deletion burden exceeding the pathogenic threshold, without altering heteroplasmy or mtDNA copy number. MTERF1 binds wild-type and deletion-bearing mitochondrial genomes indiscriminately at a site downstream of the ribosomal RNA genes and curbs transcription. Relieving this constraint broadly increased OXPHOS transcripts, thereby eliciting more respiratory output from the residual wild-type genomes. Notably, the buffering effect of MTERF1 loss extended beyond mtDNA deletions. In a counter-screen, MTERF1 loss could also restore respiratory growth in cells depleted of nuclear-encoded mitochondrial genes such as OPA1 and COX5A . Together, these findings indicate that by relieving a transcriptional constraint, MTERF1 loss compensates for reduced genome dosage, defining a strategy to enhance residual mitochondrial function in mtDNA deletion disorders and related conditions.

DOI: https://doi.org/10.64898/2026.07.16.738964

Genetics. 2026 Aug 01. pii: iyag200. [Epub ahead of print]

Ribosome-associated chaperones integrate co-translational mitochondrial protein import, stress signaling and proteostasis in Saccharomyces cerevisiae.

J Ernesto Bravo-Arévalo, Ariann E Mendoza-Martínez, Teresa Ballado, Ericka Moreno-Méndez, Alexander DeLuna, Soledad Funes.

Mitochondrial biogenesis requires the coordinated synthesis, targeting, and import of nuclear-encoded mitochondrial precursor proteins. Although ribosome-associated chaperones support co-translational protein folding, their genetic contributions to mitochondrial protein import and cellular homeostasis remain incompletely defined. Here, we investigate the roles of the nascent polypeptide-associated complex (NAC) and the ribosome-associated Hsp70 system Ssb1/2 in Saccharomyces cerevisiae. We show that NAC and Ssb1/2 have distinct yet partially overlapping functions in the handling of mitochondrial precursor proteins. Loss of NAC activates the mitochondrial retrograde pathway and enhances growth on ethanol as a non-fermentable carbon source without compromising respiratory competence, indicating metabolic adaptation rather than overt mitochondrial dysfunction. In contrast, Ssb1/2 deficiency disrupts cytosolic proteostasis, sensitizes cells to TORC1 inhibition, and impairs autophagy and mitophagy. Using a TEV protease-based import reporter, we show that Ssb1/2 promotes efficient co-translational distribution of precursor proteins, whereas NAC limits the accumulation of misfolded proteins at the mitochondrial surface. Biochemical analyses further reveal that Ssb1/2 supports the association of translating cytosolic ribosomes with the mitochondrial outer membrane, while NAC loss partially restores this interaction in the absence of Ssb1/2. Together, these findings establish NAC and Ssb1/2 as key components of an integrated network linking co-translational targeting, mitochondrial signaling, and cellular homeostasis.

Keywords: Saccharomyces cerevisiae ; Ribosome-associated chaperones; TORC1 signaling; co-translational targeting; mitochondrial protein import; proteostasis; retrograde signaling

DOI: https://doi.org/10.1093/genetics/iyag200