bims-smemid 2025-06-08 papers

bioRxiv. 2025 May 27. pii: 2025.05.13.653903. [Epub ahead of print]

Cellular metabolic state controls mitochondrial RNA kinetics.

Sean D Reardon, Clarisa Bautista, Shannon C Cole, Julien Cicero, Tatiana V Mishanina.

Human mitochondrial genome encodes essential genes for the oxidative phosphorylation (OXPHOS) complexes. These genes must be transcribed and translated in coordination with nuclear-encoded OXPHOS components to ensure correct stoichiometry during OXPHOS complex assembly in the mitochondria. While much is known about nuclear gene regulation during metabolic stresses like glucose deprivation, little is known about the accompanying transcriptional response in mitochondria. Using microscopy, roadblocking qPCR, and transcriptomics, we studied mitochondrial transcription in cells subjected to glucose deprivation, which is known to cause nuclear transcription downregulation and to activate the integrated stress response (ISR). We found that glucose deprivation stabilizes mitochondrial RNAs and slows mitochondrial transcription, effects that are quickly reversed with glucose reintroduction. Although transcriptomics revealed strong upregulation of the ISR, mitochondrial RNA stabilization was not upregulated by pharmacological activation of the ISR, but was promoted by inhibition of glycolysis, unveiling a direct connection between metabolism and regulation of mitochondrial gene expression.

DOI: https://doi.org/10.1101/2025.05.13.653903

J Biol Chem. 2025 Jun 03. pii: S0021-9258(25)02184-2. [Epub ahead of print] 110334

Mitochondrial tRNA processing defects reprogram mitochondrial and cellular homeostasis.

Gao Zhu, Yunfan He, Xincheng Li, Yun Xiao, Huisen Zhan, Maoli Duan, Min-Xin Guan.

Mitochondrial tRNA processing defects have been associated with some clinical presentations including deafness. Especially, a deafness-linked m.7516delA mutation impaired the 5' end processing of RNA precursors and mitochondrial translation. In this study, we investigated the mechanism by m.7516delA mutation induced-deficiencies mitigate organellular and cellular integrity. The m.7516delA mutation downregulated the expression of nucleus encoding subunits and upregulated assemble factors of complex IV and altered the assembly and activities of oxidative phosphorylation (OXPHOS) complexes. The impairment of OXPHOS alleviated mitochondrial quality control processes, including the imbalanced mitochondrial dynamics via increasing fission with abnormal mitochondrial morphology. The m.7516delA mutation upregulated both ubiquitin-dependent and independent mitophagy pathways, evidenced by increasing levels of Parkin, BNIP3, NIX and MFN2-ubiquitination and altering interaction between MFN2 and MUL1 or Parkin, to facilitate the degradation of severely damaged mitochondria. Strikingly, the m.7516delA mutation activated integrated stress response (ISR) pathway, evidenced by upregulation of GCN2, P-GCN2, p-eIF2α, CHOP, ATF4 and elevating the nucleus-location of ATF5 to minimizes the damages in defective mitochondria. Both activation of ISR and PINK1/Parkin mitophagy pathways ameliorate the cell homeostasis via elevating the autophagy process and upregulating apoptotic pathways. Our findings provide new insights into underlying aberrant RNA processing-induced dysfunctions reprogrammed organelles and cellular integrity.

DOI: https://doi.org/10.1016/j.jbc.2025.110334

Mol Syst Biol. 2025 Jun 05.

Pathway metabolite ratios reveal distinctive glutamine metabolism in a subset of proliferating cells.

Nancy T Santiappillai, Yue Cao, Mariam F Hakeem-Sanni, Jean Yang, Lake-Ee Quek, Andrew J Hoy.

Large-scale metabolomic analyses of pan-cancer cell line panels have provided significant insights into the relationships between metabolism and cancer cell biology. Here, we took a pathway-centric approach by transforming targeted metabolomic data into ratios to study associations between reactant and product metabolites in a panel of cancer and non-cancer cell lines. We identified five clusters of cells from various tissue origins. Of these, cells in Cluster 4 had high ratios of TCA cycle metabolites relative to pyruvate, produced more lactate yet consumed less glucose and glutamine, and greater OXPHOS activity compared to Cluster 3 cells with low TCA cycle metabolite ratios. This was due to more glutamine cataplerotic efflux and not glycolysis in cells of Cluster 4. In silico analyses of loss-of-function and drug sensitivity screens showed that Cluster 4 cells were more susceptible to gene deletion and drug targeting of glutamine metabolism and OXPHOS than cells in Cluster 3. Our results highlight the potential of pathway-centric approaches to reveal new aspects of cellular metabolism from metabolomic data.

Keywords: Cancer Cell Lines; Glucose Metabolism; Glutamine Metabolism; Metabolic Pathways; Metabolomics

DOI: https://doi.org/10.1038/s44320-025-00099-0

bioRxiv. 2025 May 16. pii: 2025.05.16.654318. [Epub ahead of print]

Impaired Complex I dysregulates neural/glial precursors and corpus callosum development revealing postnatal defects in Leigh Syndrome mice.

Sahitya Ranjan Biswas, Porter L Tomsick, Colin Kelly, Brooke A Lester, Julia P Milner, Sara N Henry, Yaris Soto, Samantha Brindley, Nicole DeFoor, Paul D Morton, Alicia M Pickrell.

Leigh syndrome (LS) is a complex, genetic mitochondrial disorder defined by neurodegenerative phenotypes with pediatric manifestation. However, recent clinical studies report behavioral phenotypes in human LS patients that are more reminiscent of neurodevelopmental delays. To determine if disruptions in epochs of rapid brain growth during infancy precede the hallmark brain lesions that arise during childhood, we evaluated neural and glial precursor cellular dynamics in a mouse model of LS. Single cell RNA sequencing along with histological and anatomical assessments were performed in NDUFS4 KO mice and compared with controls to determine the impact of Complex I deficiency on neural stem cells, their neuronal and oligodendroglial progeny, lineage progression, and overt differences in specific brain regions. Our findings show disruptions in all categories, specifically within the subventricular zone and corpus callosum. Given that LS is purely considered a neurodegenerative disease, we propose that mitochondrial dysfunction is a neurodevelopmental signature predating classic diagnosis in LS.

DOI: https://doi.org/10.1101/2025.05.16.654318