bims-mitran 2026-02-08 papers

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

bioRxiv. 2026 Jan 15. pii: 2026.01.14.699555. [Epub ahead of print]

LONP-1 deficiency causes dysregulated protein synthesis within mitochondria that is restored by mitoribosomal mutations.

Levi Ali, Avijit Mallick, Yunguang Du, Rui Li, Lihua Julie Zhu, Kuang Shen, Cole M Haynes.

Mitochondrial homeostasis is maintained by multiple molecular chaperones and proteases located within the organelle. The mitochondrial matrix-localized protease LONP-1 degrades oxidatively damaged or misfolded proteins. Importantly, LONP-1 also regulates mitochondrial DNA replication. Here, we show that mutations in C. elegans that impair LONP-1 function cause dysregulation of mitochondrial DNA replication, mitochondrial RNA transcription and protein synthesis within the mitochondrial matrix. LONP-1 deficient worms had reduced levels of oxidative phosphorylation proteins despite increased mtDNA-encoded protein synthesis. Via a forward genetic screen, we identified three mutations that restored mitochondrial function and the rate of development in lonp-1 mutants to levels comparable to those in wildtype worms. Interestingly, all three suppressor mutations were found in genes encoding mitochondrial ribosome proteins. A point mutation in the mitochondrial ribosome protein MRPS-38 restored oxidative phosphorylation in lonp-1 mutant worms. Combined, our results suggest that LONP-1 regulates mitochondrial protein synthesis and that the suppressor mutations within MRPS-38 or MRPS-15 enhance oxidative phosphorylation complex assembly by slowing translation.

DOI: https://doi.org/10.64898/2026.01.14.699555

Elife. 2026 Feb 06. pii: RP108742. [Epub ahead of print]14

Suppression of interferon signaling via small-molecule modulation of TFAM.

Dionisia Sideris, Husan Lee, Lyndsay Olson, Kalyan Nallaparaju, Keiichiro Okuyama, Jeffrey Ciavarri, Robert Lafyatis, Mads Larsen, Bo Lin, Irene Alfaras, Jason Kennerdell, Toren Finkel, Yuan Liu, Bill Chen, Lin Lyu.

The mitochondrial transcription factor A (TFAM) is essential for mitochondrial genome maintenance. It binds to mitochondrial DNA (mtDNA) and determines the abundance, packaging, and stability of the mitochondrial genome. Because its function is tightly associated with mtDNA, TFAM has a protective role in mitochondrial diseases, and supportive studies demonstrate reversal of disease phenotypes by TFAM overexpression. In addition, TFAM deficiency has been shown to cause release of mtDNA into the cytosol and activation of the cGAS/STING innate immune response pathway. As such, TFAM presents as a unique target for therapeutic intervention, but limited efforts for activators have been reported. Herein, we disclose novel TFAM small-molecule modulators with sub-micromolar activity. Our results demonstrate that these compounds result in an increase of TFAM protein levels and mtDNA copy number. This results in inhibition of a mtDNA stress-mediated inflammatory response by preventing mtDNA escape into the cytosol. Furthermore, we see beneficial effects in cellular disease models in which boosting TFAM activity has been advanced as a disease-modifying strategy including improved energetics in MELAS cybrid cells and a decrease of fibrotic markers in systemic sclerosis fibroblasts. These results highlight the therapeutic potential of using small-molecule TFAM activators in indications characterized by mitochondrial dysfunction.

Keywords: TFAM; cGAS-STING pathway; cell biology; human; interferon sinaling; mitochondria; mitochondrial DNA; small molecule

DOI: https://doi.org/10.7554/eLife.108742

bioRxiv. 2026 Jan 25. pii: 2026.01.25.701366. [Epub ahead of print]

Pol γ possesses separate metal binding sites for polymerase and strand displacement functions.

Noe Baruch-Torres, Joon Park, Josue Mora-Garduño, Arkanil Roy, Anupam Singh, G Andrés Cisneros, Luis G Brieba, Smita S Patel, Y Whitney Yin.

Accurate replication of mitochondrial genome (mtDNA) integrity, which is essential for cellular metabolism and energy supply, relies primarily on DNA polymerase gamma (Pol γ), Twinkle helicase, and mitochondrial single-stranded DNA binding protein (mtSSB). Twinkle alone exhibits little helicase activity while reports indicate that Pol γ displays from modest to limited unwinding activity. This led us to dissect Pol γ strand displacement activity using structural, biochemical and in silico approaches. Here, we show that human Pol γ carries out robust strand displacement synthesis at physiological concentrations of divalent metal ions which reveals that distinct metal-binding sites can independently regulate DNA synthesis and unwinding activities. We further showed that Pol γ can displace RNA/DNA hybrid with comparable efficiency as DNA/DNA duplex, representing a key implication on RNA primer removal to preserve mtDNA integrity. Our cryo-electron microscopy structures of Pol γ complexed with a template containing downstream dsDNA and an incoming nucleotide revealed the structural mechanism for the strand displacement activity. We identified four conformational states that represent successive stages of DNA unwinding, accompanied by coordinated rearrangement of the downstream DNA and Pol γ elements that mediate strand displacement. This work establishes biochemical and structural mechanisms of Pol γ strand displacement activity, providing fundamental insight into human mitochondrial DNA replication and integrity.
Graphical abstract:

DOI: https://doi.org/10.64898/2026.01.25.701366

Mitochondrion. 2026 Feb 04. pii: S1567-7249(26)00007-3. [Epub ahead of print]88 102117

Probability of Mitochondrial DNA heteroplasmy in different tissues from European populations.

Daniel R Cuesta-Aguirre, Ana Onieva, M Pilar Aluja, Cristina Santos.

Mitochondrial DNA (mtDNA) heteroplasmy complicates genetic analyses due to its variability across individuals and tissues. We analyzed over 400 Spanish blood samples and integrated published Massively Parallel Sequencing (MPS) data from ten additional European tissues. Heteroplasmy was tissue-specific, with skeletal muscle, kidney, and liver showing the highest levels, while the intestines, skin, and cerebellum had the lowest. Blood uniquely displayed more heteroplasmies in coding than non-coding regions. Several conserved positions not previously described as hotspots showed high frequencies. These results establish the first comprehensive tissue-specific heteroplasmic profile of the complete mitochondrial genome in a European population, improving the interpretation of mtDNA variation in forensic and biomedical contexts.

Keywords: Heteroplasmic profile; Heteroplasmy; Massively Parallel Sequencing (MPS); Mitochondrial DNA (mtDNA); Point heteroplasmy

DOI: https://doi.org/10.1016/j.mito.2026.102117