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This study aimed to determine the role of mitochondrial morphology in canonical necroptosis induced by a combination of TNF\u03b1 and zVAD (TNF\/zVAD) in H9c2 cells, rat cardiomyoblasts. Time-course analyses of mitochondrial morphology showed that mitochondria were initially shortened after the addition of TNF\/zVAD and then their length was restored, and the proportion of cells with elongated mitochondria at 12 h was larger in TNF\/zVAD-treated cells than in non-treated cells (16.3 \u00b1 0.9% vs. 8.0 \u00b1 1.2%). The knockdown of dynamin-related protein 1 (Drp1) and fission 1, fission promoters, and treatment with Mdivi-1, a Drp-1 inhibitor, had no effect on TNF\/zVAD-induced necroptosis. In contrast, TNF\/zVAD-induced necroptosis was attenuated by the knockdown of mitofusin 1\/2 (Mfn1\/2) and optic atrophy-1 (Opa1), proteins that are indispensable for mitochondrial fusion, and the attenuation of necroptosis was not canceled by treatment with Mdivi-1. The expression of TGF\u03b2-activated kinase (TAK1), a negative regulator of RIP1 activity, was upregulated and the TNF\/zVAD-induced RIP1-Ser166 phosphorylation, an index of RIP1 activity, was mitigated by the knockdown of Mfn1\/2 or Opa1. Pharmacological TAK1 inhibition attenuated the protection afforded by Mfn1\/2 and Opa1 knockdown. In conclusion, the inhibition of mitochondrial fusion increases TAK1 expression, leading to the attenuation of canonical necroptosis through the suppression of RIP1 activity.<\/jats:p>","DOI":"10.3390\/ijms25052905","type":"journal-article","created":{"date-parts":[[2024,3,4]],"date-time":"2024-03-04T05:31:12Z","timestamp":1709530272000},"page":"2905","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Downregulation of Mitochondrial Fusion Protein Expression Affords Protection from Canonical Necroptosis in H9c2 Cardiomyoblasts"],"prefix":"10.3390","volume":"25","author":[{"given":"Yuki","family":"Toda","sequence":"first","affiliation":[{"name":"Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo 060-8543, 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