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Here, we investigated mitochondrial\u2013immune remodeling in SARS-CoV-2\u2013infected lung-derived LC-HK2 cells at 48 and 96 h post-infection using confocal and high-content imaging, colocalization analysis, CellProfiler quantification, RT-qPCR, proteomics, cytokine profiling, and conditioned-medium analysis. Infection induced a time-dependent mitochondrial phenotype. At 48 hpi, cells displayed early mitochondrial stress and fission-associated signatures, including increased DRP1, transient upregulation of mitochondrial respiratory genes, and reduced MFN1\/2. At 96 hpi, mitochondria shifted toward elongated perinuclear networks, accompanied by increased fusion\/biogenesis markers and partial ISG15\u2013MFN2 colocalization, indicating a spatial association between ISG15-related antiviral\/stress responses and mitochondrial remodeling. Antiviral and ISG-related transcripts were consistently upregulated, but IFN-\u03b12 secretion remained limited, suggesting partial uncoupling between antiviral transcriptional activation and downstream interferon output. SUMO2\/3 was dynamically modulated and showed time-dependent colocalization with mitochondrial dynamics proteins and MAVS. Together, these data support a coordinated mitochondrial\u2013immune regulatory axis involving mitochondrial remodeling, ISG15-associated responses, and SUMO-dependent regulation during SARS-CoV-2 infection.<\/jats:p>","DOI":"10.3390\/v18060675","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T03:27:21Z","timestamp":1781666841000},"page":"675","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Exploring Key Regulators of Mitochondrial Dynamics and Immune Response in SARS-CoV-2 Infection"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7002-5180","authenticated-orcid":false,"given":"Thatiana Corr\u00eaa de","family":"Melo","sequence":"first","affiliation":[{"name":"Centre of Excellence in New Target Discovery (CENTD), Butantan Institute, S\u00e3o Paulo 05503-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hellen Paula","family":"Valerio","sequence":"additional","affiliation":[{"name":"Centre of Excellence in New Target Discovery (CENTD), Butantan Institute, S\u00e3o Paulo 05503-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dilza","family":"Trevisan-Silva","sequence":"additional","affiliation":[{"name":"Centre of Excellence in New Target Discovery (CENTD), Butantan Institute, S\u00e3o Paulo 05503-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcelo Medina de","family":"Souza","sequence":"additional","affiliation":[{"name":"Centre of Excellence in New Target Discovery (CENTD), Butantan Institute, S\u00e3o Paulo 05503-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda Teixeira de","family":"Melo","sequence":"additional","affiliation":[{"name":"Centre of Excellence in New Target Discovery (CENTD), Butantan Institute, S\u00e3o Paulo 05503-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7986-923X","authenticated-orcid":false,"given":"Miryam Paola","family":"Alvarez-Flores","sequence":"additional","affiliation":[{"name":"Centre of Excellence in New Target Discovery (CENTD), Butantan Institute, S\u00e3o Paulo 05503-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8919-4996","authenticated-orcid":false,"given":"Douglas Souza","family":"Oliveira","sequence":"additional","affiliation":[{"name":"Centre of Excellence in New Target Discovery (CENTD), Butantan Institute, S\u00e3o Paulo 05503-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renata Nascimento","family":"Gomes","sequence":"additional","affiliation":[{"name":"Centre of Excellence in New Target Discovery (CENTD), Butantan Institute, S\u00e3o Paulo 05503-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2046-9693","authenticated-orcid":false,"given":"Glaucia Maria","family":"Machado-Santelli","sequence":"additional","affiliation":[{"name":"Department of Cell and Developmental Biology, Institute of Biomedical Sciences (ICB-USP), University of S\u00e3o Paulo, S\u00e3o Paulo 05508-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7043-1979","authenticated-orcid":false,"given":"Beatriz Fumelli Monti","family":"Ribeiro","sequence":"additional","affiliation":[{"name":"Department of Cell and Developmental Biology, Institute of Biomedical Sciences (ICB-USP), University of S\u00e3o Paulo, S\u00e3o Paulo 05508-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viviane Fongaro","family":"Botosso","sequence":"additional","affiliation":[{"name":"Virology Laboratory, Butantan Institute, S\u00e3o Paulo 05503-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soraia Attie","family":"Calil Jorge","sequence":"additional","affiliation":[{"name":"Viral Biotechnology Laboratory, Butantan Institute, S\u00e3o Paulo 05503-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Marisa","family":"Chudzinski-Tavassi","sequence":"additional","affiliation":[{"name":"Centre of Excellence in New Target Discovery (CENTD), Butantan Institute, S\u00e3o Paulo 05503-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1038\/s41579-020-00468-6","article-title":"Coronavirus Biology and Replication: Implications for SARS-CoV-2","volume":"19","author":"Kratzel","year":"2021","journal-title":"Nat. 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