{
  "abstract": "When mammalian cells are under increased ATP demand, mitochondria segregate into two distinct subpopulations, one capable of oxidative phosphorylation (oxidative subpopulation) and another specialized in reductive synthesis of metabolic precursors (reductive subpopulation). Here we report that mitochondrial DNA (mtDNA) along with protein components of the mitochondrial nucleoid segregate to the oxidative subpopulation in response to increased ATP demand. This suggests that formation of the reductive mitochondrial subpopulation might serve to eliminate alternative uses of mitochondrial NAD(P)H when cells are under bioenergetic or nutrient stress. To examine this further, we studied mitochondria in cells exposed to low levels of glutamine. Mitochondria use glutaminase (GLS1) to maintain net glutamine uptake when cytosolic glutamine decreases, by converting glutamine to glutamate. The resulting glutamate can either be oxidized into α-ketoglutarate to enter the TCA cycle or utilized in the reductive synthesis of proline/ornithine. GLS1 can polymerize into hyperactive filaments in response to elevations in inorganic phosphate as might occur when ATP consumption exceeds production. However, when extracellular glutamine is reduced, GLS1 filaments segregated away from mtDNA, becoming colocalized with pyrroline-5-carboxylate synthase (P5CS) filaments in reductive mitochondria lacking ATP synthase markers. This cosegregation supported the ability of TGF-β signaling to enhance reductive proline/ornithine biosynthesis under low glutamine conditions despite compromising oxidative TCA cycle support from glutamine. The cosegregation of GLS1-P5CS filaments depended on continuing mitochondrial fission/fusion and occurred even in cells lacking mtDNA. Together, these data demonstrate that the reductive mitochondrial subpopulation is functional and under regulation by both metabolic demand and intercellular signal transduction.",
  "abstract_shown": true,
  "affiliations": [
    "Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065",
    "Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, NY 10065",
    "Department of Medicine, University of Chicago, Chicago, IL 60637",
    "Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 8,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Tak Shun Fung"
    },
    {
      "affs": [
        0
      ],
      "name": "Elias Tzoc-Pacheco"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Ruobing Cui"
    },
    {
      "affs": [
        0
      ],
      "name": "Shelby Brown"
    },
    {
      "affs": [
        2
      ],
      "name": "Simon Schwörer"
    },
    {
      "affs": [
        0
      ],
      "name": "Tullia Lindsten"
    },
    {
      "affs": [
        0
      ],
      "name": "Craig B. Thompson"
    },
    {
      "affs": [
        0,
        3
      ],
      "name": "Keunwoo Ryu"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/56dv800p9ej7h.bib",
  "cited_by": 0,
  "doi": "10.1073/pnas.2613074123",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13715731/",
  "id": "56dv800p9ej7h",
  "issns": [
    "0027-8424",
    "1091-6490"
  ],
  "landing_url": "https://doi.org/10.1073/pnas.2613074123",
  "language": "en",
  "licence": "CC-BY-NC-ND-4.0",
  "licence_label": "CC BY-NC-ND 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "409"
    ],
    [
      "heading",
      "Biological Sciences"
    ],
    [
      "heading",
      "Cell Biology"
    ],
    [
      "openalex",
      "1312|Mitochondrial Function and Pathology"
    ]
  ],
  "openalex": "W7223134311",
  "pdf_url": "https://www.pnas.org/doi/pdf/10.1073/pnas.2613074123",
  "pmcid": "PMC13715731",
  "pmid": "42905544",
  "published": "2026-10-21",
  "publisher": "National Academy of Sciences",
  "ris": "https://research.draconitic.com/paper/56dv800p9ej7h.ris",
  "sources": [
    {
      "first_seen": "2026-11-01T12:22:57Z",
      "native_id": "PMC13715731",
      "source": "pmc",
      "url": "https://doi.org/10.1073/pnas.2613074123"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "heading:Cell Biology",
      "subfield": "cell-biology"
    }
  ],
  "title": "Mitochondrial subpopulations promote cellular responses to changes in metabolic demand and signal transduction",
  "title_text": "Mitochondrial subpopulations promote cellular responses to changes in metabolic demand and signal transduction",
  "type": "peer-reviewed",
  "updated_at": "2026-11-01T12:22:57Z",
  "url": "https://research.draconitic.com/paper/56dv800p9ej7h",
  "venue": "Proceedings of the National Academy of Sciences of the United States of America",
  "versions": []
}