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COVID-19 may involve multiorgan damage from direct viral invasion through angiotensin-converting enzyme 2 (ACE2), through inflammatory cytokine storms, or through other secondary pathways. This study involved the analysis of publicly accessible transcriptome data from the Gene Expression Omnibus (GEO) database for identifying significant differentially expressed genes related to COVID-19 and an investigation relating to the pathways associated with mitochondrial, cardiac, hepatic, and renal toxicity in COVID-19. Significant differentially expressed genes were identified and ranked by statistical approaches, and the genes derived by biological meaning were ranked by feature importance; both were utilized as machine learning features for verification. Sample set selection for machine learning was based on the performance, sample size, imbalanced data state, and overfitting assessment. Machine learning served as a verification tool by facilitating the testing of biological hypotheses by incorporating gene list adjustment. A subsequent in-depth study for gene and pathway network analysis was conducted to explore whether COVID-19 is associated with cardiac, hepatic, and renal impairments via mitochondrial infection. The analysis showed that potential cardiac, hepatic, and renal impairments in COVID-19 are associated with ACE2, inflammatory cytokine storms, and mitochondrial pathways, suggesting potential medical interventions for COVID-19-induced multiorgan damage.<\/jats:p>","DOI":"10.1371\/journal.pone.0297664","type":"journal-article","created":{"date-parts":[[2024,1,31]],"date-time":"2024-01-31T18:36:46Z","timestamp":1706726206000},"page":"e0297664","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":11,"title":["Transcriptome and machine learning analysis of the impact of COVID-19 on mitochondria and multiorgan damage"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-0992-9066","authenticated-orcid":true,"given":"Yu-Yu","family":"Chang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7927-1636","authenticated-orcid":true,"given":"An-Chi","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,1,31]]},"reference":[{"key":"pone.0297664.ref001","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.4269\/ajtmh.21-1240","article-title":"Involvement of the liver in COVID-19: a systematic review","volume":"106","author":"JC Kariyawasam","year":"2022","journal-title":"Am J Trop Med Hyg"},{"key":"pone.0297664.ref002","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s10741-020-10008-2","article-title":"Heart failure and COVID-19","volume":"26","author":"F Bader","year":"2021","journal-title":"Heart Fail Rev"},{"key":"pone.0297664.ref003","doi-asserted-by":"crossref","first-page":"895","DOI":"10.2147\/IDR.S288869","article-title":"Renal involvement in COVID-19: a review of the literature","volume":"14","author":"MG Migliaccio","year":"2021","journal-title":"Infect Drug Resist"},{"key":"pone.0297664.ref004","doi-asserted-by":"crossref","first-page":"446","DOI":"10.3390\/jcm10030446","article-title":"Multi-organ involvement in COVID-19: beyond pulmonary manifestations","volume":"10","author":"V Thakur","year":"2021","journal-title":"J Clin Med"},{"key":"pone.0297664.ref005","doi-asserted-by":"crossref","first-page":"m4470","DOI":"10.1136\/bmj.m4470","article-title":"Long COVID: damage to multiple organs presents in young, low risk patients","volume":"371","author":"G. 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