{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T20:17:16Z","timestamp":1792441036334,"version":"4.5.0"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T00:00:00Z","timestamp":1781222400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Tumor heterogeneity is the key driver of disease progression and therapeutic resistance in clear cell renal cell carcinoma (ccRCC). Within this landscape, mitochondrial (MT) heterogeneity has emerged as a critical but poorly understood feature. This study identified a specific manifestation of MT heterogeneity termed \u201cnucleo-mitochondrial expression asymmetry (NMA)\u201d. It is characterized by a dysregulated burst of mitochondrial DNA (mtDNA)-encoded genes compared to the nuclear genome, marking a pivotal tipping point in tumor proliferation and spatial reconstruction.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We employed an integrative multi-omics approach combining single-cell RNA sequencing (scRNA-seq), spatial transcriptomics (stRNA-seq), and mass spectrometry imaging (MSI)-based spatial metabolomics from the Tongji Renal Cell Carcinoma (TJ-RCC) cohort. To identify and characterize the profound NMA malignant subpopulations, we utilized Gaussian Mixture Model (GMM) clustering, CytoTRACE 2 for differentiation potential, and scFEA for metabolic flux inference. We implemented neighborhood and pseudo-spatiotemporal map (pSM) analyses to quantify spatial reconstruction. We validated these findings through mitochondrially encoded cytochrome\n                      <jats:italic>c<\/jats:italic>\n                      oxidase I (MT-CO1) immunohistochemistry (IHC) in an independent cohort of 53 patients.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We identified a unique malignant subpopulation (C0) defined by NMA, where nucleo-mitochondrial coordination significantly decreased to R\u00a0=\u00a00.30 compared to R\u00a0=\u00a00.50 in other clusters. C0 functioned as a proliferative engine, exhibiting the highest ribosomal activity, peak differentiation potential, and concentrated G2M\/S-phase activity. Metabolic modeling and MSI revealed that C0-dominant regions act as metabolic hubs, correlating with total metabolic flux (R\u00a0=\u00a00.631) and the physical accumulation of tricarboxylic acid (TCA) cycle intermediates. Spatially, C0 abundance was highly predictive of global MT gene scores (R\u00a0=\u00a00.852). As ccRCC progressed, NMA-driven niches underwent a dramatic reconstruction: transitioning from an \u201cimmune-active core\u201d in the early stages to stroma-shielded \u201cmetabolic islands\u201d in the advanced stages. Furthermore, we observed a resurgence of NMA and the C0 subpopulation in metastatic lesions. Clinical validation confirmed that MT-CO1 protein levels\u2014a histological proxy for NMA\u2014positively correlated with the proliferation marker Ki67 (r = 0.702) and served as an independent prognostic factor for overall survival.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study characterized NMA as a hallmark of ccRCC progression and spatial niche reconstruction, offering a novel, clinically actionable framework for metabolic risk stratification via MT-CO1.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1838182","type":"journal-article","created":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T11:05:07Z","timestamp":1781262307000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Nucleo-mitochondrial asymmetry profiles the proliferative engine and spatial niche reconstruction in clear cell renal cell carcinoma"],"prefix":"10.3389","volume":"17","author":[{"given":"Shansen","family":"Peng","sequence":"first","affiliation":[{"name":"Affiliated Meizhou Hospital of Shantou University Medical College","place":["Meizhou, China"]},{"name":"Department of Urology, Meizhou People\u2019s Hospital (Meizhou Academy of Medical Sciences)","place":["Meizhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhouzhou","family":"Xie","sequence":"additional","affiliation":[{"name":"Affiliated Meizhou Hospital of Shantou University Medical College","place":["Meizhou, China"]},{"name":"Department of Urology, Meizhou People\u2019s Hospital (Meizhou Academy of Medical Sciences)","place":["Meizhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Hu","sequence":"additional","affiliation":[{"name":"Affiliated Meizhou Hospital of Shantou University Medical College","place":["Meizhou, 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Shantou University Medical College","place":["Meizhou, China"]},{"name":"Department of Urology, Meizhou People\u2019s Hospital (Meizhou Academy of Medical Sciences)","place":["Meizhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guihao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Affiliated Meizhou Hospital of Shantou University Medical College","place":["Meizhou, China"]},{"name":"Department of Urology, Meizhou People\u2019s Hospital (Meizhou Academy of Medical Sciences)","place":["Meizhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nanhui","family":"Chen","sequence":"additional","affiliation":[{"name":"Affiliated Meizhou Hospital of Shantou University Medical College","place":["Meizhou, China"]},{"name":"Department of Urology, Meizhou People\u2019s Hospital (Meizhou Academy of Medical Sciences)","place":["Meizhou, 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