bims-smemid Biomed News
on Stress metabolism in mitochondrial dysfunction
Issue of 2026–11–15
two papers selected by
Deepti Mudartha, The International Institute of Molecular Mechanisms and Machines
  1. Copper transport to mitochondria by SLC25A3 contributes to skeletal myoblast differentiation and is required for survival of differentiated myotubes.
  2. A convergent proline biosynthetic step couples cell wall integrity to virulence in Cryptococcus neoformans.
  1. J Biol Chem. 2026 Nov 12. pii: S0021-9258(26)02614-1. [Epub ahead of print] 113742
    Copper transport to mitochondria by SLC25A3 contributes to skeletal myoblast differentiation and is required for survival of differentiated myotubes.
    Alexandra M Perez, Jason D Fivush, Bailey M Cordill, Nathan Ferguson, Yu Zhang, Allison T Mezzell, Isaac Johnson, Ushodaya Mattam, Omar Chaudhry, Karleigh Porter, Saanvi Maadaadi, Dina Secic, Megan E Bischoff, Karthickeyan Chella Krishnan, Rhett A Kovall, John T Cunningham, Maria F Czyzyk-Krzeska, Katherine E Vest.
      Differentiation of skeletal muscle is associated with increased mitochondrial biogenesis and reliance on oxidative phosphorylation (OXPHOS). The terminal enzyme complex in the electron transport chain, cytochrome c oxidase (COX), requires copper for its assembly and activity, and copper delivery to mitochondria is essential for OXPHOS. However, when mitochondrial copper becomes essential during skeletal myoblast differentiation is not known. Here, we show that inducing genetic deficiency of the mitochondrial copper and phosphate carrier SLC25A3 prior to myoblast differentiation leads to the formation of smaller myotubes, but SLC25A3 deficiency induced in mature myotubes leads to cell death and detachment. Both phenotypes are recapitulated upon genetic knockdown of COX17, a key chaperone for COX copper cofactor assembly, and by chemical inhibition of COX. Importantly, myotube death caused by SLC25A3 deficiency is reversed by copper supplementation. Expression of an SLC25A3 isoform A variant that is equivalent to a variant in isoform B that exclusively transports copper also rescues myotube viability. Taken together these data support a model wherein SLC25A3 is critical for survival in mature myotubes, likely due to its role in providing copper to COX.
    Keywords:  copper; copper transport; cytochrome c oxidase (Complex IV); myogenesis; skeletal muscle
    DOI:  https://doi.org/10.1016/j.jbc.2026.113742
  2. mBio. 2026 Nov 10. e0257426
    A convergent proline biosynthetic step couples cell wall integrity to virulence in Cryptococcus neoformans.
    Yujin Lee, Minjae Lee, Seun Kang, Hyunjin Cha, Doyeon Won, Kyung-Ah Lee, Won-Jae Lee, Kyung-Tae Lee, Yong-Sun Bahn.
      Metabolic adaptation is essential for the pathogenicity of the opportunistic fungus Cryptococcus neoformans. Although amino acid biosynthesis pathways are critical fitness determinants in fungal pathogens, the physiological contributions of proline biosynthesis remain incompletely understood, with most studies focusing on proline catabolism. Here, we characterized the proline biosynthetic enzymes Pro1, Pro2, and Pro3 in C. neoformans. Proline is produced by two routes that converge on Δ1-pyrroline-5-carboxylate (P5C): a de novo pathway from glutamate via Pro1 and Pro2, and an arginine-derived bypass via Car1 and Car2-both requiring Pro3 for the final reduction of P5C to proline. Although all biosynthetic mutants were strictly auxotrophic for proline, their requirements for virulence differed markedly: in a murine infection model, pro1Δ and pro2Δ mutants retained full virulence, whereas pro3Δ exhibited significantly attenuated virulence accompanied by growth defects and impaired cell wall integrity. Genetic disruption of P5C-generating routes partially restored distinct pro3Δ phenotypes, with PRO2 deletion alleviating delayed growth, and combined PRO2 and CAR2 deletion partially restoring cell size, while cell wall defects remained unresolved. This dissociation indicates that growth requires proper balance of P5C-generating metabolic flux, whereas cell wall integrity depends on a distinct mechanism that is not resolved by blocking P5C production. Together, these findings identify Pro3 as a metabolic gatekeeper coupling proline biosynthesis to cell wall homeostasis, establishing the biosynthetic branch of proline metabolism as a previously unappreciated determinant of fungal pathobiology.
    IMPORTANCE: Cryptococcus neoformans is a leading cause of fungal meningitis worldwide, causing life-threatening infections primarily in immunocompromised individuals. To survive within the human host, this pathogen must synthesize essential nutrients through de novo biosynthesis when host-derived supplies are limited. Although proline catabolism has been studied extensively in fungal pathogens, the physiological roles of individual proline biosynthetic enzymes in human fungal pathogens remain incompletely understood. Here, we show that the terminal enzyme Pro3, but not the upstream enzymes Pro1 and Pro2, is selectively required for full virulence in a murine model. Pro3 supports pathobiological fitness by promoting growth under host-relevant conditions and maintaining cell wall integrity. These findings highlight the importance of proline biosynthesis beyond nutrient production and link this pathway to growth, cell wall integrity, and virulence in C. neoformans.
    Keywords:  Cryptococcus neoformans; amino acid metabolism; cell wall integrity; fungal pathogen; proline biosynthesis
    DOI:  https://doi.org/10.1128/mbio.02574-26
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