bims-omitod 2025-12-07 papers

Nat Commun. 2025 Dec 03.

Vacuolar-type H+-ATPase-mediated extra-organellar buffering resolves mitochondrial dysfunction.

Geoffray Monteuuis, Ryan Awadhpersad, Daan van der Kolk, Sachin K Singh, Tuula A Nyman, Alina Malyutina, Nicola Zamboni, Kari Moisio, Juhana Juutila, Ville Hietakangas, Sara Seneca, Christopher J Carroll, Christopher B Jackson.

Mitochondrial dysfunction underlies a wide range of human diseases, including primary mitochondrial disorders, neurodegeneration, cancer, and ageing. To preserve cellular homeostasis, organisms have evolved adaptive mechanisms that coordinate nuclear and mitochondrial gene expression. Here, we use genome-wide CRISPR knockout screening to identify cell fitness pathways that support survival under impaired mitochondrial protein synthesis. The strongest suppressor of aberrant mitochondrial translation defects - besides a compendium of known mitochondrial translation quality control factors - is the loss of the vacuolar-type H+-ATPase (v-ATPase), a key regulator of intracellular acidification, nutrient sensing, and growth signaling. We show that partial v-ATPase loss reciprocally modulates mitochondrial membrane potential (ΔΨm) and cristae structure in both cancer cell lines and mitochondrial disease patient-derived models. Our findings uncover an extra-organellar buffering mechanism whereby partial v-ATPase inhibition mitigates mitochondrial dysfunction by altering pH homeostasis and driving metabolic rewiring as a protective response that promotes cell fitness.

DOI: https://doi.org/10.1038/s41467-025-66656-1

Sci Rep. 2025 Dec 02. 15(1): 43031

Examining saliva proteomic dynamics in mitochondrial diseases from a perspective of intrinsic health.

Jiaying Zhao, Bowen Xu, Tianhui Huang, Sewanou Hermann Honfo, Caroline Trumpff, Martin Picard, Alan A Cohen, Molei Liu.

Mitochondrial disease (MitoD), a clinical condition caused by genetic mitochondrial defects, affects cellular energy transformation and alters multiple dimensions of health. Recently, we collected a longitudinal saliva proteomics data set consisting of six healthy controls and six MitoD subjects throughout the awakening response process. We undertook three independent unsupervised or inferential approaches to characterize proteome dynamics and assessed their ability to separate MitoD individuals from controls. First, we designed a permutation test to detect the global difference in the proteomic co-regulation structure between healthy and unhealthy subjects. Second, we performed non-linear embedding and cluster analysis on elasticity to capture a more complicated relationship between health and the proteome. Third, we developed a machine learning algorithm to extract low-dimensional representations of the proteome dynamic and use them to cluster subjects into healthy and unhealthy groups without any knowledge of their true status. All three methods showed clear differences between MitoD individuals and controls. Our results revealed a significant and consistent association between MitoD status and the saliva proteome at multiple levels during the awakening response, including its dynamic change, co-regulation structure, and elasticity. Pipelines such as those shown here are the first step toward establishing interpretable and accurate framework for detecting signals related to mitochondrial disease progression from proteome dynamics.

DOI: https://doi.org/10.1038/s41598-025-23879-y

Nat Commun. 2025 Dec 04. 16(1): 10891

Mitochondria-targeted gene delivery using fluorinated lipid nanoparticles to alleviate Leber's hereditary optic neuropathy.

Yi Wang, Min Zhao, Hai-Xin Xie, Hao-Yuan Yu, Jing-Song Yang, Lu-Xin Qie, Na-Hui Liu, Jia-Qi Chen, Zi-Juan Yi, Tian-Jiao Zhou, Lei Xing, Xian Wu Cheng, Hu-Lin Jiang.

Mutations in mitochondrial DNA (mtDNA) lead to various mitochondrial diseases for which no cure is currently available. Despite the promising potential of mtDNA correction to treat these disorders, the double mitochondrial membranes have proven to be a tough barrier to overcome. Here, we develop fluorinated lipid nanoparticles with a mitochondrial targeting sequence (F-M-LNP) to overcome the mitochondrial barrier by virtue of their high affinity for mitochondrial membranes, thereby effectively introducing gene into mitochondria. Through the rational design of ionizable lipid structures, we synthesize 16 lipid nanoparticles (LNPs) with varying degrees of fluorination and investigate the key structural features required for efficient mitochondria-targeted gene delivery. As fluorinated ionizable lipid-mediated mitochondrial transport is independent of mitochondrial membrane potential (MMP), F-M-LNPs deliver gene to mitochondria under pathological conditions where MMP is impaired, resulting in a 3.8-fold increase in functional protein expression compared to non-fluorinated LNPs. In a male mouse model of genetically induced mitochondrial disease, F-M-LNP demonstrate functional complementation of mutant mtDNA, alleviating disease symptoms. Together, our results show that modifying vectors with fluorinated groups offers valuable tools for correcting mitochondrial genome defects.

DOI: https://doi.org/10.1038/s41467-025-65874-x

Sci Adv. 2025 Dec 05. 11(49): eaea8481

Targeting multiple genetic defects of mitochondrial diseases with a single bacterial lipoate protein ligase.

Zhijuan Hu, Junru Yu, Ziwei Liu, Min Jiang, An-Ping Zeng.

Metabolic disorders caused by defects in energy metabolism can lead to many life-threatening diseases; their therapy remains elusive in most cases. Conventional gene therapy relies on the "one gene for one genetic defect" strategy. Here, we demonstrate a more efficient strategy to target multiple genetic defects with a single gene intervention. Specifically, we used a bacterial lipoate protein ligase involved in protein lipoylation to rescue mitochondrial dysfunctions in human lipoylation pathway (LIPT2, LIAS, and LIPT1), lipoyl precursor supply (MECR), and sulfur insertion accessary partner (FDX1). The efficacy and safety of Escherichia coli-derived LplA or Bacillus subtilis-derived LplJ were validated in human cells and mouse models. LplA knock-in mice exhibited normal health with enhanced energy expenditure. Overexpressing LplA through a mating strategy rescued embryonic lethality in Lipt1-/- mutants, yielding viable offspring with normal body weight, energy expenditure, tissue morphology, and biochemical profile. Our work highlights how evolutionary differences in biosynthetic pathways between humans and bacteria can be leveraged for cross-species therapeutic innovations.

DOI: https://doi.org/10.1126/sciadv.aea8481