bims-smemid 2025-03-02 papers

Res Sq. 2025 Feb 14. pii: rs.3.rs-5961609. [Epub ahead of print]

A Quantitative Approach to Mapping Mitochondrial Specialization and Plasticity.

Martin Picard, Anna Monzel, Jack Devine, Darshana Kapri, Jose Enriquez, Caroline Trumpff.

Mitochondria are a diverse family of organelles that specialize to accomplish complimentary functions 1-3. All mitochondria share general features, but not all mitochondria are created equal 4.Here we develop a quantitative pipeline to define the degree of molecular specialization among different mitochondrial phenotypes - or mitotypes. By distilling hundreds of validated mitochondrial genes/proteins into 149 biologically interpretable MitoPathway scores (MitoCarta 3.0 5) the simple mitotyping pipeline allows investigators to quantify and interpret mitochondrial diversity and plasticity from transcriptomics or proteomics data across a variety of natural and experimental contexts. We show that mouse and human multi-organ mitotypes segregate along two main axes of mitochondrial specialization, contrasting anabolic (liver) and catabolic (brain) tissues. In cultured primary human fibroblasts exhibiting robust time-dependent and treatment-induced metabolic plasticity 6-8, we demonstrate how the mitotype of a given cell type recalibrates i) over time in parallel with hallmarks of aging, and ii) in response to genetic, pharmacological, and metabolic perturbations. Investigators can now use MitotypeExplorer.org and the associated code to visualize, quantify and interpret the multivariate space of mitochondrial biology.

DOI: https://doi.org/10.21203/rs.3.rs-5961609/v1

J Biol Chem. 2025 Feb 25. pii: S0021-9258(25)00198-X. [Epub ahead of print] 108349

Methionine cycle inhibition disrupts antioxidant metabolism and reduces glioblastoma cell survival.

Emma C Rowland, Matthew D'Antuono, Anna Jermakowicz, Nagi G Ayad.

Glioblastoma (GBM) is a highly aggressive primary malignant adult brain tumor that inevitably recurs with a fatal prognosis. This is due in part to metabolic reprogramming that allows tumors to evade treatment. Therefore, we must uncover the pathways mediating these adaptations to develop novel and effective treatments. We searched for genes that are essential in GBM cells as measured by a whole-genome pan-cancer CRISPR screen available from DepMap and identified the methionine metabolism genes MAT2A and AHCY. We conducted genetic knockdown, evaluated mitochondrial respiration, and performed targeted metabolomics to study the function of these genes in GBM. We demonstrate that MAT2A or AHCY knockdown induces oxidative stress, hinders cellular respiration, and reduces the survival of GBM cells. Furthermore, selective MAT2a or AHCY inhibition reduces GBM cell viability, impairs oxidative metabolism, and shifts the cellular metabolic profile towards oxidative stress and cell death. Mechanistically, MAT2a and AHCY regulate spare respiratory capacity, the redox buffer cystathionine, lipid and amino acid metabolism, and prevent oxidative damage in GBM cells. Our results point to the methionine metabolic pathway as a novel vulnerability point in GBM. Significance We demonstrated that methionine metabolism maintains antioxidant production to facilitate pro-tumorigenic ROS signaling and GBM tumor cell survival. Importantly, targeting this pathway in GBM has the potential to reduce tumor growth and improve survival in patients.

Keywords: glioblastoma; lipid peroxidation; metabolism; metabolomics; methionine; mitochondria; oxidative stress

DOI: https://doi.org/10.1016/j.jbc.2025.108349

Cells. 2025 Feb 11. pii: 257. [Epub ahead of print]14(4):

How the Topology of the Mitochondrial Inner Membrane Modulates ATP Production.

Raquel Adams, Nasrin Afzal, Mohsin Saleet Jafri, Carmen A Mannella.

Cells in heart muscle need to generate ATP at or near peak capacity to meet their energy demands. Over 90% of this ATP comes from mitochondria, strategically located near myofibrils and densely packed with cristae to concentrate ATP generation per unit volume. However, a consequence of dense inner membrane (IM) packing is that restricted metabolite diffusion inside mitochondria may limit ATP production. Under physiological conditions, the flux of ATP synthase is set by ADP levels in the matrix, which in turn depends on diffusion-dependent concentration of ADP inside cristae. Computer simulations show how ADP diffusion and consequently rates of ATP synthesis are modulated by IM topology, in particular (i) number, size, and positioning of crista junctions that connect cristae to the IM boundary region, and (ii) branching of cristae. Predictions are compared with the actual IM topology of a cardiomyocyte mitochondrion in which cristae vary systematically in length and morphology. The analysis indicates that this IM topology decreases but does not eliminate the "diffusion penalty" on ATP output. It is proposed that IM topology normally attenuates mitochondrial ATP output under conditions of low workload and can be regulated by the cell to better match ATP supply to demand.

Keywords: ATP synthesis; cristae; electron tomography; membrane topology; metabolic modeling; metabolite diffusion; mitochondria

DOI: https://doi.org/10.3390/cells14040257