bims-smemid 2025-12-21 papers

J Biol Chem. 2025 Dec 17. pii: S0021-9258(25)02922-9. [Epub ahead of print] 111070

The cytochrome c oxidase subunit COX6B1 is required for redox-sensitive early assembly and late stabilization of complex IV.

Kristýna Čunátová, Marek Vrbacký, Michal Knězů, Alena Pecinová, Lukáš Alán, Josef Houštěk, Erika Fernández-Vizarra, Tomáš Mráček, Petr Pecina.

COX6B1 is a nuclear-encoded subunit of the human mitochondrial cytochrome c oxidase (cIV) located in its intermembrane space-facing region. The relevance of COX6B1 in mitochondrial physiopathology was highlighted by the missense pathogenic variants associated with cIV deficiency. Despite the assigned COX6B1 role as a late incorporation subunit, the COX6B1 human cell line knock-out (KO) exhibited a total loss of cIV. To get a deeper insight into the mechanisms driving the lack of cIV assembly or destabilization in the absence of COX6B1, we used the COX6B1 KO cell background to express alternative oxidase and COX6B1 pathogenic variants. These analyses uncovered that the COX6B1 subunit is indispensable for redox-sensitive early cIV assembly steps, besides its contribution to the stabilization of cIV in the late assembly stages. In addition, we have evidenced the incorporation of partially assembled cIV modules directly into supercomplex structures, supporting the 'cooperative assembly' model for respiratory chain biogenesis.

Keywords: COX; COX6B1; COX6B2; OXPHOS assembly; alternative oxidase; cIV; complex IV; cytochrome c oxidase; mitochondrial deficiency; respiratory chain supercomplexes

DOI: https://doi.org/10.1016/j.jbc.2025.111070

Mol Aspects Med. 2025 Dec 18. pii: S0098-2997(25)00102-5. [Epub ahead of print]107 101438

Serine metabolism in the central nervous system: advances and challenges on a conditionally essential amino acid.

Natasa Kustrimovic, Valentina Rabattoni, Daniele Riva, Zoraide Motta, Silvia Sacchi, Loredano Pollegioni.

Once considered a non-essential amino acid, L-serine (L-Ser) is now recognized as conditionally essential in the brain, orchestrating a complex network of metabolic and signalling pathways. L-Ser provides carbon units to the one-carbon metabolism, supporting nucleotide synthesis and methylation reactions, and serves as a precursor for phosphatidylserine and sphingolipids. L-Ser plays crucial roles in glutathione and heme metabolism and interfaces with mitochondrial one-carbon pathways, thereby linking it to energy production, redox homeostasis, and epigenetic regulation. Its conversion into glycine and D-serine further supports neurotransmission, synaptic plasticity, and cognitive functions. Throughout the lifespan, L-Ser and its derivatives contribute to maintaining neuronal and glial homeostasis. However, fundamental questions remain regarding how L-Ser biosynthesis, transport, and compartmentalization are coordinated in the intact brain and how their dysregulation contributes to disease. Current knowledge largely derives from cancer biology or in vitro models, and translating these insights to the central nervous system poses major challenges. The lack of specific tools to monitor L-Ser flux in vivo, limited understanding of post-translational regulation of key enzymes and incomplete mapping of transport mechanisms across the blood-brain barrier still hampers deeper mechanistic and translational insight. This review compiles the most recent evidence, emphasizing the translational relevance of L-Ser-based interventions and underscoring the urgent need for systematic clinical trials to fully evaluate its therapeutic potential.

Keywords: D-serine; L-serine; Metabolism; Neurotransmission; Phosphorylated pathway; Serinosome

DOI: https://doi.org/10.1016/j.mam.2025.101438

EMBO Mol Med. 2025 Dec 19.

Mutant CHCHD10 disrupts cytochrome c oxidation and activates mitochondrial retrograde signaling.

Márcio Augusto Campos-Ribeiro, Erminia Donnarumma, Hendrik Nolte, Paul Cobine, Elodie Vimont, Dusanka Milenkovic, Juan Diego Hernandez-Camacho, Francina Langa-Vives, Etienne Kornobis, Esthel Pénard, Sonny Yde, Thomas Langer, Véronique Paquis-Flucklinger, Timothy Wai.

Mutations in CHCHD10, a mitochondrial intermembrane space (IMS) protein implicated in proteostasis and cristae maintenance, cause mitochondrial disease. Knock-in mice modeling the human CHCHD10S59L variant associated with ALS-FTD develop a mitochondrial cardiomyopathy driven by CHCHD10 aggregation and activation of the mitochondrial integrated stress response (mtISR). We show that cardiac dysfunction is associated with dual defects originating at the onset of disease: (1) bioenergetic failure linked to impaired mitochondrial copper homeostasis and cytochrome c oxidation, and (2) maladaptive mtISR signaling via the OMA1-DELE1-HRI axis. Using protease-inactive Oma1E324Q/E324Q knock-in mice, we show that blunting mtISR in Chchd10S55L/+ mice delays cardiomyopathy onset without rescuing CHCHD10 insolubility, cristae defects or OXPHOS impairment. Proteomic profiling of insoluble mitochondrial proteins in Chchd10S55L/+ mice reveals widespread disruptions of mitochondrial proteostasis, including IMS proteins involved in cytochrome c biogenesis. Defective respiration in mutant mitochondria is rescued by the addition of cytochrome c, pinpointing IMS proteostasis disruption as a key pathogenic mechanism. Thus, mutant CHCHD10 insolubility compromises metabolic resilience by impairing bioenergetics and stress adaptation, offering new perspectives for the development of therapeutic targets.

Keywords: CHCHD10; Cardiomyopathy; Cytochrome c; Mitochondrial Disease; OMA1

DOI: https://doi.org/10.1038/s44321-025-00358-5

EMBO J. 2025 Dec 17.

The transaminase-ω-amidase pathway senses oxidative stress to control glutamine metabolism and α-ketoglutarate levels in endothelial cells.

Oxidative stress is a major driver of cardiovascular disease; however, the fast changes in cellular metabolism caused by short-lived reactive oxygen species (ROS) remain ill-defined. Here, we characterized changes in the endothelial cell metabolome in response to acute oxidative challenges and identified novel redox-sensitive metabolic enzymes. H2O2 selectively increased the amount of α-ketoglutaramate (αKGM), a largely uncharacterized metabolite produced by glutamine transamination and an unrecognized intermediate of endothelial glutamine catabolism. In addition, H2O2 impaired the catalytic activity of nitrilase-like 2 ω-amidase (NIT2), the enzyme that converts αKGM to α-ketoglutarate (αKG), by the reversible oxidation of specific cysteine residues. Moreover, a NIT2 gene variant exhibited decreased expression in humans and was associated with increased plasma αKGM concentration. Endothelial-specific knockout of NIT2 in mice increased cellular αKGM levels and impaired angiogenesis. Further, NIT2 depletion impaired endothelial cell proliferation, sprouting, and induced senescence. In conclusion, we uncover NIT2 as a redox-sensitive enzyme of the glutamine transaminase-ω-amidase pathway that acts as a metabolic switch modulating endothelial glutamine metabolism in mice and humans.

Keywords: Endothelial Cells; Glutamine Metabolism; Oxidative Stress; α-Ketoglutaramate; α-Ketoglutarate

DOI: https://doi.org/10.1038/s44318-025-00642-7